bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–01–22
forty-nine papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington's disease.
  2. Tissue adaptation and clonal segregation of human memory T cells in barrier sites.
  3. IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.
  4. Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis.
  5. Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
  6. Initiation of type 2 immunity at barrier surfaces.
  7. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.
  8. Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene.
  9. Spontaneous behaviour is structured by reinforcement without explicit reward.
  10. A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.
  11. Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.
  12. Resident memory T cells develop regional dialects.
  13. BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases.
  14. Lymphatic vessels in bone support regeneration after injury.
  15. Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis.
  16. People.
  17. Functional T cells are capable of supernumerary cell division and longevity.
  18. The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.
  19. Exhausted T cells in tumors gain suppressor activity and can restrain immunity.
  20. Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.
  21. Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs.
  22. Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1.
  23. An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.
  24. Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling.
  25. Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation.
  26. Transformer for one stop interpretable cell type annotation.
  27. Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases.
  28. A tissue atlas of ulcerative colitis revealing evidence of sex-dependent differences in disease-driving inflammatory cell types and resistance to TNF inhibitor therapy.
  29. DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.
  30. START smuggling CoQ to fight ferroptosis.
  31. Epigenetic resetting in the human germ line entails histone modification remodeling.
  32. The β-selection step shapes T-cell identity.
  33. Linking genetic variants to cellular function and disease.
  34. Plasma membrane lipid diffusion.
  35. Mono- and biallelic variant effects on disease at biobank scale.
  36. Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
  37. A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.
  38. Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition.
  39. Nanobody-driven signaling reveals the core receptor complex in root nodule symbiosis.
  40. Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution.
  41. The variant senescence-associated secretory phenotype induced by centrosome amplification constitutes a pathway that activates hypoxia-inducible factor-1α.
  42. Sex-specificity of the C. elegans metabolome.
  43. Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation.
  44. DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer.
  45. Immune cells' ability to persist and replicate long outlives species lifespan.
  46. Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.
  47. Actin limits egg aneuploidies associated with female reproductive aging.
  48. Inferring visual space from ultra-fine extra-retinal knowledge of gaze position.
  49. IL-1α-releasing TH17 cells live long and prosper.
  1. Nat Commun. 2023 Jan 17. 14(1): 282
    Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington's disease.
    Ayano Matsushima, Sergio Sebastian Pineda, Jill R Crittenden, Hyeseung Lee, Kyriakitsa Galani, Julio Mantero, Geoffrey Tombaugh, Manolis Kellis, Myriam Heiman, Ann M Graybiel.
      Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington's disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD. In human HD, striosomal indirect-pathway SPNs are the most depleted SPN population. In mouse HD models, the transcriptomic distinctiveness of striosome-matrix SPNs is diminished more than that of direct-indirect pathway SPNs. Furthermore, the loss of striosome-matrix distinction is more prominent within indirect-pathway SPNs. These results open the possibility that the canonical direct-indirect pathway and striosome-matrix compartments are differentially compromised in late and early stages of disease progression, respectively, differentially contributing to the symptoms, thus calling for distinct therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-022-35752-x
  2. Nat Immunol. 2023 Jan 19.
    Tissue adaptation and clonal segregation of human memory T cells in barrier sites.
    Maya M L Poon, Daniel P Caron, Zicheng Wang, Steven B Wells, David Chen, Wenzhao Meng, Peter A Szabo, Nora Lam, Masaru Kubota, Rei Matsumoto, Adeeb Rahman, Eline T Luning Prak, Yufeng Shen, Peter A Sims, Donna L Farber.
      T lymphocytes migrate to barrier sites after exposure to pathogens, providing localized immunity and long-term protection. Here, we obtained blood and tissues from human organ donors to examine T cells across major barrier sites (skin, lung, jejunum), associated lymph nodes, lymphoid organs (spleen, bone marrow), and in circulation. By integrating single-cell protein and transcriptome profiling, we demonstrate that human barrier sites contain tissue-resident memory T (TRM) cells that exhibit site-adapted profiles for residency, homing and function distinct from circulating memory T cells. Incorporating T cell receptor and transcriptome analysis, we show that circulating memory T cells are highly expanded, display extensive overlap between sites and exhibit effector and cytolytic functional profiles, while TRM clones exhibit site-specific expansions and distinct functional capacities. Together, our findings indicate that circulating T cells are more disseminated and differentiated, while TRM cells exhibit tissue-specific adaptation and clonal segregation, suggesting that strategies to promote barrier immunity require tissue targeting.
    DOI:  https://doi.org/10.1038/s41590-022-01395-9
  3. Nat Commun. 2023 Jan 19. 14(1): 321
    IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.
    Julie M Mazet, Jagdish N Mahale, Orion Tong, Robert A Watson, Ana Victoria Lechuga-Vieco, Gabriela Pirgova, Vivian W C Lau, Moustafa Attar, Lada A Koneva, Stephen N Sansom, Benjamin P Fairfax, Audrey Gérard.
      IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.
    DOI:  https://doi.org/10.1038/s41467-023-35948-9
  4. Nat Commun. 2023 Jan 19. 14(1): 319
    Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis.
    Jae-Seung Moon, Shady Younis, Nitya S Ramadoss, Radhika Iyer, Khushboo Sheth, Orr Sharpe, Navin L Rao, Stephane Becart, Julie A Carman, Eddie A James, Jane H Buckner, Kevin D Deane, V Michael Holers, Susan M Goodman, Laura T Donlin, Mark M Davis, William H Robinson.
      The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB+CD8+ cells are present in RA synovium. These findings suggest that cytotoxic CD8+ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.
    DOI:  https://doi.org/10.1038/s41467-022-35264-8
  5. Nat Cancer. 2023 Jan 16.
    Cancer cells resistant to immune checkpoint blockade acquire interferon-associated epigenetic memory to sustain T cell dysfunction.
    Jingya Qiu, Bihui Xu, Darwin Ye, Diqiu Ren, Shangshang Wang, Joseph L Benci, Yuanming Xu, Hemant Ishwaran, Jean-Christophe Beltra, E John Wherry, Junwei Shi, Andy J Minn.
      Prolonged interferon (IFN) signaling in cancer cells can promote resistance to immune checkpoint blockade (ICB). How cancer cells retain effects of prolonged IFN stimulation to coordinate resistance is unclear. We show that, across human and/or mouse tumors, immune dysfunction is associated with cancer cells acquiring epigenetic features of inflammatory memory. Here, inflammatory memory domains, many of which are initiated by chronic IFN-γ, are maintained by signal transducer and activator of transcription (STAT)1 and IFN regulatory factor (IRF)3 and link histone 3 lysine 4 monomethylation (H3K4me1)-marked chromatin accessibility to increased expression of a subset of IFN-stimulated genes (ISGs). These ISGs include the RNA sensor OAS1 that amplifies type I IFN (IFN-I) and immune inhibitory genes. Abrogating cancer cell IFN-I signaling restores anti-programmed cell death protein 1 (PD1) response by increasing IFN-γ in immune cells, promoting dendritic cell and CD8+ T cell interactions, and expanding T cells toward effector-like states rather than exhausted states. Thus, cancer cells acquire inflammatory memory to augment a subset of ISGs that promote and predict IFN-driven immune dysfunction.
    DOI:  https://doi.org/10.1038/s43018-022-00490-y
  6. Mucosal Immunol. 2023 Jan 12. pii: S1933-0219(22)01181-3. [Epub ahead of print]
    Initiation of type 2 immunity at barrier surfaces.
    Margaret M McDaniel, Heber I Lara, Jakob von Moltke.
      Although seemingly unrelated, parasitic worms, venoms, and allergens all induce a type 2 immune response. The effector functions and clinical features of type 2 immunity are well defined, but fundamental questions about the initiation of type 2 immunity remain unresolved. How are the enormously diverse type 2 stimuli first detected? How are type 2 helper T cells (Th2) primed and regulated? And how do mechanisms of type 2 initiation vary across tissues? Here, we review the common themes governing type 2 immune sensing and explore aspects of T cell priming and effector reactivation that make Th2 cells a unique T helper lineage. Throughout the review we emphasize the importance of non-hematopoietic cells and highlight how the unique anatomy and physiology of each barrier tissue shapes mechanisms of type 2 immune initiation.
    Keywords:  ILC2; Th2; chemosensing; protease; type 2 immunity
    DOI:  https://doi.org/10.1016/j.mucimm.2022.11.002
  7. Nat Cell Biol. 2023 Jan;25(1): 30-41
    Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing.
    Carl A Mitchell, Evgenia V Verovskaya, Fernando J Calero-Nieto, Oakley C Olson, James W Swann, Xiaonan Wang, Aurélie Hérault, Paul V Dellorusso, Si Yi Zhang, Arthur Flohr Svendsen, Eric M Pietras, Sietske T Bakker, Theodore T Ho, Berthold Göttgens, Emmanuelle Passegué.
      Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1β (IL-1β) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.
    DOI:  https://doi.org/10.1038/s41556-022-01053-0
  8. Nat Commun. 2023 Jan 19. 14(1): 307
    Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as an adiposity gene.
    Katherine A Kentistou, Jian'an Luan, Laura B L Wittemans, Catherine Hambly, Lucija Klaric, Zoltán Kutalik, John R Speakman, Nicholas J Wareham, Timothy J Kendall, Claudia Langenberg, James F Wilson, Peter K Joshi, Nicholas M Morton.
      Obesity remains an unmet global health burden. Detrimental anatomical distribution of body fat is a major driver of obesity-mediated mortality risk and is demonstrably heritable. However, our understanding of the full genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. To address this, we impute whole-body imaging adiposity phenotypes in UK Biobank from the 4,366 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. Using these imputed phenotypes in 392,535 participants yielded hundreds of genome-wide significant associations, six of which replicate in independent cohorts. The leading causal gene candidate, ADAMTS14, is further investigated in a mouse knockout model. Concordant with the human association data, the Adamts14-/- mice exhibit reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Thus, we show that phenotypic imputation at scale offers deeper biological insights into the genetics of human adiposity that could lead to therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-022-35563-0
  9. Nature. 2023 Jan 18.
    Spontaneous behaviour is structured by reinforcement without explicit reward.
    Jeffrey E Markowitz, Winthrop F Gillis, Maya Jay, Jeffrey Wood, Ryley W Harris, Robert Cieszkowski, Rebecca Scott, David Brann, Dorothy Koveal, Tomasz Kula, Caleb Weinreb, Mohammed Abdal Monium Osman, Sandra Romero Pinto, Naoshige Uchida, Scott W Linderman, Bernardo L Sabatini, Sandeep Robert Datta.
      Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences1,2. However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour.
    DOI:  https://doi.org/10.1038/s41586-022-05611-2
  10. Nat Commun. 2023 Jan 17. 14(1): 267
    A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification.
    B Edginton-White, A Maytum, S G Kellaway, D K Goode, P Keane, I Pagnuco, S A Assi, L Ames, M Clarke, P N Cockerill, B Göttgens, J B Cazier, C Bonifer.
      Developmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem (ES) cells, which can be adapted to any ES cell derived cell type. We show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals terminating at signalling responsive transcription factors. Our work provides an important resource for studies of hematopoietic specification and highlights the mechanisms of how and where extrinsic signals program a cell type-specific chromatin landscape driving hematopoietic differentiation.
    DOI:  https://doi.org/10.1038/s41467-023-35910-9
  11. Nat Immunol. 2023 Jan 19.
    Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia.
    Yingyue Zhou, Mari Tada, Zhangying Cai, Prabhakar S Andhey, Amanda Swain, Kelly R Miller, Susan Gilfillan, Maxim N Artyomov, Masaki Takao, Akiyoshi Kakita, Marco Colonna.
      The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
    DOI:  https://doi.org/10.1038/s41590-022-01403-y
  12. Nat Immunol. 2023 Jan 19.
    Resident memory T cells develop regional dialects.
    Nicholas J Maurice, Stephen C Jameson.
      
    DOI:  https://doi.org/10.1038/s41590-022-01416-7
  13. Nat Commun. 2023 Jan 17. 14(1): 266
    BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases.
    Saaket Agrawal, Marcus D R Klarqvist, Nathaniel Diamant, Takara L Stanley, Patrick T Ellinor, Nehal N Mehta, Anthony Philippakis, Kenney Ng, Melina Claussnitzer, Steven K Grinspoon, Puneet Batra, Amit V Khera.
      For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.
    DOI:  https://doi.org/10.1038/s41467-022-35704-5
  14. Cell. 2023 Jan 19. pii: S0092-8674(22)01574-4. [Epub ahead of print]186(2): 382-397.e24
    Lymphatic vessels in bone support regeneration after injury.
    Lincoln Biswas, Junyu Chen, Jessica De Angelis, Amit Singh, Charlotte Owen-Woods, Zhangfan Ding, Joan Mane Pujol, Naveen Kumar, Fanxin Zeng, Saravana K Ramasamy, Anjali P Kusumbe.
      Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11+ CXCR4+ pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.
    Keywords:  3D imaging; IL6; aging; bone; hematopoiesis; injury; lymphangiocrine; lymphatic vessels; regeneration; stress
    DOI:  https://doi.org/10.1016/j.cell.2022.12.031
  15. Nat Commun. 2023 Jan 17. 14(1): 75
    Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis.
    Xuexiang Han, Ningqiang Gong, Lulu Xue, Margaret M Billingsley, Rakan El-Mayta, Sarah J Shepherd, Mohamad-Gabriel Alameh, Drew Weissman, Michael J Mitchell.
      Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a preclinical model of liver fibrosis, AA-T3A-C12 enables ~65% silencing of heat shock protein 47, a therapeutic target primarily expressed by activated fibroblasts, which is 2-fold more potent than MC3, leading to significantly reduced collagen deposition and liver fibrosis. These results demonstrate the potential of AA-lipidoids for targeted RNA delivery to activated fibroblasts. Furthermore, these synthetic methods and screening strategies open a new avenue to develop and discover potent lipidoids with targeting properties, which can potentially enable RNA delivery to a range of cell and tissue types that are challenging to access using traditional lipid nanoparticle formulations.
    DOI:  https://doi.org/10.1038/s41467-022-35637-z
  16. Nat Biotechnol. 2023 Jan;41(1): 156
    People.
      
    DOI:  https://doi.org/10.1038/s41587-022-01629-z
  17. Nature. 2023 Jan 18.
    Functional T cells are capable of supernumerary cell division and longevity.
    Andrew G Soerens, Marco Künzli, Clare F Quarnstrom, Milcah C Scott, Lee Swanson, J J Locquiao, Hazem E Ghoneim, Dietmar Zehn, Benjamin Youngblood, Vaiva Vezys, David Masopust.
      Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1-3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime-boost-boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.
    DOI:  https://doi.org/10.1038/s41586-022-05626-9
  18. Nat Commun. 2023 Jan 16. 14(1): 240
    The metabolite alpha-ketobutyrate extends lifespan by promoting peroxisomal function in C. elegans.
    Nan Wu, Yi-Cheng Ma, Xin-Qian Gong, Pei-Ji Zhao, Yong-Jian Jia, Qiu Zhao, Jia-Hong Duan, Cheng-Gang Zou.
      Metabolism is intimately linked to aging. There is a growing number of studies showing that endogenous metabolites may delay aging and improve healthspan. Through the analysis of existing transcriptome data, we discover a link between activation of the transsulfuration pathway and a transcriptional program involved in peroxisome function and biogenesis in long-lived glp-1(e2141ts) mutant Caenorhabditis elegans worms. Subsequently, we show that supplementation with α-ketobutyrate, an intermediate of the transsulfuration pathway, extends lifespan in wild-type worms. Alpha-ketobutyrate augments the production of NAD+ via the lactate dehydrogenase LDH-1, leading to SIR-2.1/SIRT1-mediated enhanced peroxisome function and biogenesis, along with a concomitant increase in the expression of acox-1.2/ACOX1 in the peroxisomal fatty acid β-oxidation pathway. ACOX-1.2/ACOX1 promotes H2O2 formation, thereby resulting in activation of SKN-1/NRF2. This transcription factor in turn extends the lifespan of worms by driving expression of autophagic and lysosomal genes. Finally, we show that α-ketobutyrate also delays the cellular senescence in fibroblast cells through the SIRT1-ACOX1-H2O2-NRF2 pathway. This finding uncovers a previously unknown role for α-ketobutyrate in organismal lifespan and healthspan by coordinating the NAD+-SIRT1 signaling and peroxisomal function.
    DOI:  https://doi.org/10.1038/s41467-023-35899-1
  19. Nat Immunol. 2023 Jan 17.
    Exhausted T cells in tumors gain suppressor activity and can restrain immunity.
      
    DOI:  https://doi.org/10.1038/s41590-022-01409-6
  20. Mol Cell. 2023 Jan 11. pii: S1097-2765(22)01212-6. [Epub ahead of print]
    Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells.
    Dania Riegel, Elena Romero-Fernández, Malte Simon, Akinbami Raphael Adenugba, Katrin Singer, Roman Mayr, Florian Weber, Mark Kleemann, Charles D Imbusch, Marina Kreutz, Benedikt Brors, Ines Ugele, Jens M Werner, Peter J Siska, Christian Schmidl.
      Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
    Keywords:  CRISPR activation; CRISPR interference; T cell exhaustion; cancer immunology; chromatin accessibility; enhancer; gene regulation; single-cell ATAC-seq; tumor-infiltrating T cells
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.029
  21. Nat Commun. 2023 Jan 18. 14(1): 300
    Kaposi's sarcoma-associated herpesvirus induces specialised ribosomes to efficiently translate viral lytic mRNAs.
    James C Murphy, Elena M Harrington, Sophie Schumann, Elton J R Vasconcelos, Timothy J Mottram, Katherine L Harper, Julie L Aspden, Adrian Whitehouse.
      Historically, ribosomes were viewed as unchanged homogeneous macromolecular machines with no regulatory capacity for mRNA translation. An emerging concept is that heterogeneity of ribosomal composition exists, exerting a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct specialised ribosomes that actively regulate mRNA translation. Viruses lack their own translational machinery and impose high translational demands on the host during replication. We explore the possibility that KSHV manipulates ribosome biogenesis producing specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic replication. We demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and the KSHV ORF11 protein, with small ribosomal subunit precursor complexes during lytic replication. BUD23 depletion resulted in significantly reduced viral gene expression, culminating in dramatic reduction of infectious virion production. Ribosome profiling demonstrated BUD23 is essential for reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the downstream coding sequence. Results provide mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes facilitating efficient translation of viral mRNAs.
    DOI:  https://doi.org/10.1038/s41467-023-35914-5
  22. Nat Commun. 2023 Jan 19. 14(1): 310
    Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1.
    Michelle M Conti, Rui Li, Michelle A Narváez Ramos, Lihua Julie Zhu, Thomas G Fazzio, Jennifer A Benanti.
      Ordered cell cycle progression is coordinated by cyclin dependent kinases (CDKs). CDKs often phosphorylate substrates at multiple sites clustered within disordered regions. However, for most substrates, it is not known which phosphosites are functionally important. We developed a high-throughput approach, Phosphosite Scanning, that tests the importance of each phosphosite within a multisite phosphorylated domain. We show that Phosphosite Scanning identifies multiple combinations of phosphosites that can regulate protein function and reveals specific phosphorylations that are required for phosphorylation at additional sites within a domain. We applied this approach to the yeast transcription factor Hcm1, a conserved regulator of mitotic genes that is critical for accurate chromosome segregation. Phosphosite Scanning revealed a complex CDK-regulatory circuit that mediates Cks1-dependent phosphorylation of key activating sites in vivo. These results illuminate the mechanism of Hcm1 activation by CDK and establish Phosphosite Scanning as a powerful tool for decoding multisite phosphorylated domains.
    DOI:  https://doi.org/10.1038/s41467-023-36035-9
  23. Nat Immunol. 2023 Jan 19.
    An epithelial cell-derived metabolite tunes immunoglobulin A secretion by gut-resident plasma cells.
    Simona Ceglia, Alyssa Berthelette, Kelsey Howley, Yun Li, Benedikt Mortzfeld, Shakti K Bhattarai, Nicole K H Yiew, Ying Xu, Robert Brink, Jason G Cyster, Lora V Hooper, Gwendalyn J Randolph, Vanni Bucci, Andrea Reboldi.
      Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.
    DOI:  https://doi.org/10.1038/s41590-022-01413-w
  24. Cell Res. 2023 Jan 20.
    Human endoderm stem cells reverse inflammation-related acute liver failure through cystatin SN-mediated inhibition of interferon signaling.
    Yilin Xu, Jinglin Wang, Haozhen Ren, Hao Dai, Ying Zhou, Xiongzhao Ren, Yang Wang, Sisi Feng, Xiaogang Deng, Jiaying Wu, Tianlong Fu, Tengfei Nie, Haifeng He, Tongkun Wei, Bing Zhu, Lijian Hui, Bin Li, Jing Wang, Hongyan Wang, Luonan Chen, Xiaolei Shi, Xin Cheng.
      Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.
    DOI:  https://doi.org/10.1038/s41422-022-00760-5
  25. Nat Commun. 2023 Jan 18. 14(1): 83
    Inflammatory and infectious upper respiratory diseases associate with 41 genomic loci and type 2 inflammation.
    FINNGEN
      Inflammatory and infectious upper respiratory diseases (ICD-10: J30-J39), such as diseases of the sinonasal tract, pharynx and larynx, are growing health problems yet their genomic similarity is not known. We analyze genome-wide association to eight upper respiratory diseases (61,195 cases) among 260,405 FinnGen participants, meta-analyzing diseases in four groups based on an underlying genetic correlation structure. Aiming to understand which genetic loci contribute to susceptibility to upper respiratory diseases in general and its subtypes, we detect 41 independent genome-wide significant loci, distinguishing impact on sinonasal or pharyngeal diseases, or both. Fine-mapping implicated non-synonymous variants in nine genes, including three linked to immune-related diseases. Phenome-wide analysis implicated asthma and atopic dermatitis at sinonasal disease loci, and inflammatory bowel diseases and other immune-mediated disorders at pharyngeal disease loci. Upper respiratory diseases also genetically correlated with autoimmune diseases such as rheumatoid arthritis, autoimmune hypothyroidism, and psoriasis. Finally, we associated separate gene pathways in sinonasal and pharyngeal diseases that both contribute to type 2 immunological reaction. We show shared heritability among upper respiratory diseases that extends to several immune-mediated diseases with diverse mechanisms, such as type 2 high inflammation.
    DOI:  https://doi.org/10.1038/s41467-022-33626-w
  26. Nat Commun. 2023 Jan 14. 14(1): 223
    Transformer for one stop interpretable cell type annotation.
    Jiawei Chen, Hao Xu, Wanyu Tao, Zhaoxiong Chen, Yuxuan Zhao, Jing-Dong J Han.
      Consistent annotation transfer from reference dataset to query dataset is fundamental to the development and reproducibility of single-cell research. Compared with traditional annotation methods, deep learning based methods are faster and more automated. A series of useful single cell analysis tools based on autoencoder architecture have been developed but these struggle to strike a balance between depth and interpretability. Here, we present TOSICA, a multi-head self-attention deep learning model based on Transformer that enables interpretable cell type annotation using biologically understandable entities, such as pathways or regulons. We show that TOSICA achieves fast and accurate one-stop annotation and batch-insensitive integration while providing biologically interpretable insights for understanding cellular behavior during development and disease progressions. We demonstrate TOSICA's advantages by applying it to scRNA-seq data of tumor-infiltrating immune cells, and CD14+ monocytes in COVID-19 to reveal rare cell types, heterogeneity and dynamic trajectories associated with disease progression and severity.
    DOI:  https://doi.org/10.1038/s41467-023-35923-4
  27. Sci Immunol. 2023 Jan 20. 8(79): eabp9765
    Species-specific self-DNA detection mechanisms by mammalian cyclic GMP-AMP synthases.
    Kenta Mosallanejad, Stephanie N Kennedy, Kristin M Bahleda, Kailey M Slavik, Wen Zhou, Apurva A Govande, Dustin C Hancks, Philip J Kranzusch, Jonathan C Kagan.
      The mechanisms by which innate immune receptors mediate self-nonself discrimination are unclear. In this study, we found species-specific molecular determinants of self-DNA reactivity by cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS). Human cGAS contained a catalytic domain that was intrinsically self-DNA reactive and stimulated interferon responses in diverse cell types. This reactivity was prevented by an upstream amino (N)-terminal domain. The cGAS proteins from several nonhuman primate species exhibited a similar pattern of self-DNA reactivity in cells, but chimpanzee cGAS was inactive even when its amino-terminal domain was deleted. In contrast, the N terminus of mouse cGAS promoted self-DNA reactivity. When expressed within tumors, only self-DNA-reactive cGAS proteins protected mice from tumor-induced lethality. In vitro studies of DNA- or chromatin-induced cGAS activation did not reveal species-specific activities that correlate with self-DNA reactivity observed in macrophages. Cell biological analysis revealed that self-DNA reactivity by human cGAS, but not mouse cGAS, correlated with localization to mitochondria. We found that epitope tag positions affected self-DNA reactivity in cells and that DNA present in cell lysates undermines the reliability of cGAS biochemical fractionations. These studies reveal species-specific diversity of cGAS functions, even within the primate lineage, and highlight experimental considerations for the study of this innate immune receptor.
    DOI:  https://doi.org/10.1126/sciimmunol.abp9765
  28. Sci Adv. 2023 Jan 20. 9(3): eadd1166
    A tissue atlas of ulcerative colitis revealing evidence of sex-dependent differences in disease-driving inflammatory cell types and resistance to TNF inhibitor therapy.
    Aaron T Mayer, Derek R Holman, Anav Sood, Utkarsh Tandon, Salil S Bhate, Sunil Bodapati, Graham L Barlow, Jeff Chang, Sarah Black, Erica C Crenshaw, Alexander N Koron, Sarah E Streett, Sanjiv S Gambhir, William J Sandborn, Brigid S Boland, Trevor Hastie, Robert Tibshirani, John T Chang, Garry P Nolan, Christian M Schürch, Stephan Rogalla.
      Although literature suggests that resistance to TNF inhibitor (TNFi) therapy in patients with ulcerative colitis (UC) is partially linked to immune cell populations in the inflamed region, there is still substantial uncertainty underlying the relevant spatial context. Here, we used the highly multiplexed immunofluorescence imaging technology CODEX to create a publicly browsable tissue atlas of inflammation in 42 tissue regions from 29 patients with UC and 5 healthy individuals. We analyzed 52 biomarkers on 1,710,973 spatially resolved single cells to determine cell types, cell-cell contacts, and cellular neighborhoods. We observed that cellular functional states are associated with cellular neighborhoods. We further observed that a subset of inflammatory cell types and cellular neighborhoods are present in patients with UC with TNFi treatment, potentially indicating resistant niches. Last, we explored applying convolutional neural networks (CNNs) to our dataset with respect to patient clinical variables. We note concerns and offer guidelines for reporting CNN-based predictions in similar datasets.
    DOI:  https://doi.org/10.1126/sciadv.add1166
  29. Nat Commun. 2023 Jan 18. 14(1): 287
    DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation.
    Yunyun An, Xin Zhao, Ziteng Zhang, Zhaohua Xia, Mengqi Yang, Li Ma, Yu Zhao, Gang Xu, Shunda Du, Xiang'an Wu, Shuowen Zhang, Xin Hong, Xin Jin, Kun Sun.
      Plasma cell-free DNA (cfDNA) are small molecules generated through a non-random fragmentation procedure. Despite commendable translational values in cancer liquid biopsy, however, the biology of cfDNA, especially the principles of cfDNA fragmentation, remains largely elusive. Through orientation-aware analyses of cfDNA fragmentation patterns against the nucleosome structure and integration with multidimensional functional genomics data, here we report a DNA methylation - nuclease preference - cutting end - size distribution axis, demonstrating the role of DNA methylation as a functional molecular regulator of cfDNA fragmentation. Hence, low-level DNA methylation could increase nucleosome accessibility and alter the cutting activities of nucleases during DNA fragmentation, which further leads to variation in cutting sites and size distribution of cfDNA. We further develop a cfDNA ending preference-based metric for cancer diagnosis, whose performance has been validated by multiple pan-cancer datasets. Our work sheds light on the molecular basis of cfDNA fragmentation towards broader applications in cancer liquid biopsy.
    DOI:  https://doi.org/10.1038/s41467-023-35959-6
  30. Nat Cell Biol. 2023 Jan 19.
    START smuggling CoQ to fight ferroptosis.
    Deguang Liang, Xuejun Jiang.
      
    DOI:  https://doi.org/10.1038/s41556-022-01044-1
  31. Sci Adv. 2023 Jan 18. 9(3): eade1257
    Epigenetic resetting in the human germ line entails histone modification remodeling.
    Wolfram H Gruhn, Walfred W C Tang, Sabine Dietmann, João P Alves-Lopes, Christopher A Penfold, Frederick C K Wong, Navin B Ramakrishna, M Azim Surani.
      Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genes and transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCs exhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signatures at most genes and TEs and the acquisition of a neutral or paused epigenetic state without transcriptional activation. Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such as evolutionarily young TEs and some developmental genes, which require H3K9me3 and H3K27me3, respectively, for efficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presents an exemplary balanced system relying on local maintenance of heterochromatic features and a lack of inductive cues.
    DOI:  https://doi.org/10.1126/sciadv.ade1257
  32. Nature. 2023 Jan;613(7944): 440-442
    The β-selection step shapes T-cell identity.
    Ellen V Rothenberg.
      
    Keywords:  Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-00025-0
  33. Nat Biotechnol. 2023 Jan;41(1): 21
    Linking genetic variants to cellular function and disease.
    Alexandra Despang.
      
    DOI:  https://doi.org/10.1038/s41587-022-01647-x
  34. Nat Cell Biol. 2023 Jan;25(1): 6
    Plasma membrane lipid diffusion.
    Melina Casadio.
      
    DOI:  https://doi.org/10.1038/s41556-022-01076-7
  35. Nature. 2023 Jan;613(7944): 519-525
    Mono- and biallelic variant effects on disease at biobank scale.
    FinnGen
      Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.
    DOI:  https://doi.org/10.1038/s41586-022-05420-7
  36. Nat Cell Biol. 2023 Jan 19.
    Mitochondria regulate intracellular coenzyme Q transport and ferroptotic resistance via STARD7.
    Soni Deshwal, Mashun Onishi, Takashi Tatsuta, Tim Bartsch, Eileen Cors, Katharina Ried, Kathrin Lemke, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Coenzyme Q (or ubiquinone) is a redox-active lipid that serves as universal electron carrier in the mitochondrial respiratory chain and antioxidant in the plasma membrane limiting lipid peroxidation and ferroptosis. Mechanisms allowing cellular coenzyme Q distribution after synthesis within mitochondria are not understood. Here we identify the cytosolic lipid transfer protein STARD7 as a critical factor of intracellular coenzyme Q transport and suppressor of ferroptosis. Dual localization of STARD7 to the intermembrane space of mitochondria and the cytosol upon cleavage by the rhomboid protease PARL ensures the synthesis of coenzyme Q in mitochondria and its transport to the plasma membrane. While mitochondrial STARD7 preserves coenzyme Q synthesis, oxidative phosphorylation function and cristae morphogenesis, cytosolic STARD7 is required for the transport of coenzyme Q to the plasma membrane and protects against ferroptosis. A coenzyme Q variant competes with phosphatidylcholine for binding to purified STARD7 in vitro. Overexpression of cytosolic STARD7 increases ferroptotic resistance of the cells, but limits coenzyme Q abundance in mitochondria and respiratory cell growth. Our findings thus demonstrate the need to coordinate coenzyme Q synthesis and cellular distribution by PARL-mediated STARD7 processing and identify PARL and STARD7 as promising targets to interfere with ferroptosis.
    DOI:  https://doi.org/10.1038/s41556-022-01071-y
  37. Sci Signal. 2023 Jan 17. 16(768): eadd6702
    A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.
    Hyunbae Kim, Zhenfeng Song, Ren Zhang, Brandon S J Davies, Kezhong Zhang.
      The endoplasmic reticulum (ER)-tethered, liver-enriched stress sensor CREBH is processed in response to increased energy demands or hepatic stress to release an amino-terminal fragment that functions as a transcription factor for hepatic genes encoding lipid and glucose metabolic factors. Here, we discovered that the carboxyl-terminal fragment of CREBH (CREBH-C) derived from membrane-bound, full-length CREBH was secreted as a hepatokine in response to fasting or hepatic stress. Phosphorylation of CREBH-C mediated by the kinase CaMKII was required for efficient secretion of CREBH-C through exocytosis. Lipoprotein lipase (LPL) mediates the lipolysis of circulating triglycerides for tissue uptake and is inhibited by a complex consisting of angiopoietin-like (ANGPTL) 3 and ANGPTL8. Secreted CREBH-C blocked the formation of ANGPTL3-ANGPTL8 complexes, leading to increased LPL activity in plasma and metabolic tissues in mice. CREBH-C administration promoted plasma triglyceride clearance and partitioning into peripheral tissues and mitigated hypertriglyceridemia and hepatic steatosis in mice fed a high-fat diet. Individuals with obesity had higher circulating amounts of CREBH-C than control individuals, and human CREBH loss-of-function variants were associated with dysregulated plasma triglycerides. These results identify a stress-induced, secreted protein fragment derived from CREBH that functions as a hepatokine to stimulate LPL activity and triglyceride homeostasis.
    DOI:  https://doi.org/10.1126/scisignal.add6702
  38. Nat Commun. 2023 Jan 19. 14(1): 332
    Uncovering the mechanism for aggregation in repeat expanded RNA reveals a reentrant transition.
    Ofer Kimchi, Ella M King, Michael P Brenner.
      RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. However, the mechanism for aggregation-including how aggregation properties change with sequence and environmental conditions-remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington's disease, and enabling the rational design of programmable RNA condensates.
    DOI:  https://doi.org/10.1038/s41467-023-35803-x
  39. Science. 2023 Jan 20. 379(6629): 272-277
    Nanobody-driven signaling reveals the core receptor complex in root nodule symbiosis.
    Henriette Rübsam, Christina Krönauer, Nikolaj B Abel, Hongtao Ji, Damiano Lironi, Simon B Hansen, Marcin Nadzieja, Marie V Kolte, Dörte Abel, Noor de Jong, Lene H Madsen, Huijun Liu, Jens Stougaard, Simona Radutoiu, Kasper R Andersen.
      Understanding the composition and activation of multicomponent receptor complexes is a challenge in biology. To address this, we developed a synthetic approach based on nanobodies to drive assembly and activation of cell surface receptors and apply the concept by manipulating receptors that govern plant symbiosis with nitrogen-fixing bacteria. We show that the Lotus japonicus Nod factor receptors NFR1 and NFR5 constitute the core receptor complex initiating the cortical root nodule organogenesis program as well as the epidermal program controlling infection. We find that organogenesis signaling is mediated by the intracellular kinase domains whereas infection requires functional ectodomains. Finally, we identify evolutionarily distant barley receptors that activate root nodule organogenesis, which could enable engineering of biological nitrogen-fixation into cereals.
    DOI:  https://doi.org/10.1126/science.ade9204
  40. Nat Commun. 2023 Jan 17. 14(1): 268
    Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution.
    Laureano Tomás-Daza, Llorenç Rovirosa, Paula López-Martí, Andrea Nieto-Aliseda, François Serra, Ainoa Planas-Riverola, Oscar Molina, Rebecca McDonald, Cedric Ghevaert, Esther Cuatrecasas, Dolors Costa, Mireia Camós, Clara Bueno, Pablo Menéndez, Alfonso Valencia, Biola M Javierre.
      Long-range interactions between regulatory elements and promoters are key in gene transcriptional control; however, their study requires large amounts of starting material, which is not compatible with clinical scenarios nor the study of rare cell populations. Here we introduce low input capture Hi-C (liCHi-C) as a cost-effective, flexible method to map and robustly compare promoter interactomes at high resolution. As proof of its broad applicability, we implement liCHi-C to study normal and malignant human hematopoietic hierarchy in clinical samples. We demonstrate that the dynamic promoter architecture identifies developmental trajectories and orchestrates transcriptional transitions during cell-state commitment. Moreover, liCHi-C enables the identification of disease-relevant cell types, genes and pathways potentially deregulated by non-coding alterations at distal regulatory elements. Finally, we show that liCHi-C can be harnessed to uncover genome-wide structural variants, resolve their breakpoints and infer their pathogenic effects. Collectively, our optimized liCHi-C method expands the study of 3D chromatin organization to unique, low-abundance cell populations, and offers an opportunity to uncover factors and regulatory networks involved in disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-35911-8
  41. Aging Cell. 2023 Jan 20. e13766
    The variant senescence-associated secretory phenotype induced by centrosome amplification constitutes a pathway that activates hypoxia-inducible factor-1α.
    Selwin K Wu, Juliana Ariffin, Shu Chian Tay, Remigio Picone.
      The senescence-associated secretory phenotype (SASP) can promote paracrine invasion while suppressing tumour growth, thus generating complex phenotypic outcomes. Likewise, centrosome amplification can induce proliferation arrest yet also facilitate tumour invasion. However, the eventual fate of cells with centrosome amplification remains elusive. Here, we report that centrosome amplification induces a variant of SASP, which constitutes a pathway activating paracrine invasion. The centrosome amplification-induced SASP is non-canonical as it lacks the archetypal detectable DNA damage and prominent NF-κB activation, but involves Rac activation and production of reactive oxygen species. Consequently, it induces hypoxia-inducible factor 1α and associated genes, including pro-migratory factors such as ANGPTL4. Of note, cellular senescence can either induce tumourigenesis through paracrine signalling or conversely suppress tumourigenesis through p53 induction. By analogy, centrosome amplification-induced SASP may therefore be one reason why extra centrosomes promote malignancy in some experimental models but are neutral in others.
    Keywords:  ANGPTL4; GEF Trio; HIF-1α; Rac; centrosome; microtubule organising center; paracrine invasion; reactive oxygen species; sasp; senescence
    DOI:  https://doi.org/10.1111/acel.13766
  42. Nat Commun. 2023 Jan 19. 14(1): 320
    Sex-specificity of the C. elegans metabolome.
    Russell N Burkhardt, Alexander B Artyukhin, Erin Z Aprison, Brian J Curtis, Bennett W Fox, Andreas H Ludewig, Diana Fajardo Palomino, Jintao Luo, Amaresh Chaturbedi, Oishika Panda, Chester J J Wrobel, Victor Baumann, Douglas S Portman, Siu Sylvia Lee, Ilya Ruvinsky, Frank C Schroeder.
      Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.
    DOI:  https://doi.org/10.1038/s41467-023-36040-y
  43. Nat Commun. 2023 Jan 17. 14(1): 265
    Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation.
    Wanzun Lin, Li Chen, Haojiong Zhang, Xianxin Qiu, Qingting Huang, Fangzhu Wan, Ziyu Le, Shikai Geng, Anlan Zhang, Sufang Qiu, Long Chen, Lin Kong, Jiade J Lu.
      The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.
    DOI:  https://doi.org/10.1038/s41467-022-35710-7
  44. Nat Commun. 2023 Jan 17. 14(1): 276
    DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer.
    Maria Zhivagui, Areebah Hoda, Noelia Valenzuela, Yi-Yu Yeh, Jason Dai, Yudou He, Shuvro P Nandi, Burcak Otlu, Bennett Van Houten, Ludmil B Alexandrov.
      Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures previously attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of primary mouse embryonic fibroblasts, human foreskin fibroblasts, and human epidermal keratinocytes.
    DOI:  https://doi.org/10.1038/s41467-023-35876-8
  45. Nature. 2023 Jan 18.
    Immune cells' ability to persist and replicate long outlives species lifespan.
      
    Keywords:  Ageing; Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-022-04529-z
  46. Exp Mol Med. 2023 Jan 19.
    Site-specific ubiquitination of VDAC1 restricts its oligomerization and mitochondrial DNA release in liver fibrosis.
    Ne N Wu, Lifeng Wang, Lu Wang, Xihui Xu, Gary D Lopaschuk, Yingmei Zhang, Jun Ren.
      Mitochondrial DNA (mtDNA) released through protein oligomers, such as voltage-dependent anion channel 1 (VDAC1), triggers innate immune activation and thus contributes to liver fibrosis. Here, we investigated the role of Parkin, an important regulator of mitochondria, and its regulation of VDAC1-mediated mtDNA release in liver fibrosis. The circulating mitochondrial DNA (mtDNA) and protein levels of liver Parkin and VDAC1 were upregulated in patients with liver fibrosis. A 4-week CCl4 challenge induced release of mtDNA, activation of STING signaling, a decline in autophagy, and apoptosis in mouse livers, and the knockout of Parkin aggravated these effects. In addition, Parkin reduced mtDNA release and prevented VDAC1 oligomerization in a manner dependent on its E3 activity in hepatocytes. We found that site-specific ubiquitination of VDAC1 at lysine 53 by Parkin interrupted VDAC1 oligomerization and prevented mtDNA release into the cytoplasm under stress. The ubiquitination-defective VDAC1 K53R mutant predominantly formed oligomers that resisted suppression by Parkin. Hepatocytes expressing VDAC1 K53R exhibited mtDNA release and thus activated the STING signaling pathway in hepatic stellate cells, and this effect could not be abolished by Parkin. We propose that the ubiquitination of VDAC1 at a specific site by Parkin confers protection against liver fibrosis by interrupting VDAC1 oligomerization and mtDNA release.
    DOI:  https://doi.org/10.1038/s12276-022-00923-9
  47. Sci Adv. 2023 Jan 20. 9(3): eadc9161
    Actin limits egg aneuploidies associated with female reproductive aging.
    Sam Dunkley, Binyam Mogessie.
      Aging-related centromeric cohesion loss underlies premature separation of sister chromatids and egg aneuploidy in reproductively older females. Here, we show that F-actin maintains chromatid association after cohesion deterioration in aged eggs. F-actin disruption in aged mouse eggs exacerbated untimely dissociation of sister chromatids, while its removal in young eggs induced extensive chromatid separation events generally only seen in advanced reproductive ages. In young eggs containing experimentally reduced cohesion, F-actin removal accelerated premature splitting and scattering of sister chromatids in a microtubule dynamics-dependent manner, suggesting that actin counteracts chromatid-pulling spindle forces. Consistently, F-actin stabilization restricted scattering of unpaired chromatids generated by complete degradation of centromeric cohesion proteins. We conclude that actin mitigates egg aneuploidies arising from age-related cohesion depletion by limiting microtubule-driven separation and dispersion of sister chromatids. This is supported by our finding that spindle-associated F-actin structures are disrupted in eggs of reproductively older females.
    DOI:  https://doi.org/10.1126/sciadv.adc9161
  48. Nat Commun. 2023 Jan 17. 14(1): 269
    Inferring visual space from ultra-fine extra-retinal knowledge of gaze position.
    Zhetuo Zhao, Ehud Ahissar, Jonathan D Victor, Michele Rucci.
      It has long been debated how humans resolve fine details and perceive a stable visual world despite the incessant fixational motion of their eyes. Current theories assume these processes to rely solely on the visual input to the retina, without contributions from motor and/or proprioceptive sources. Here we show that contrary to this widespread assumption, the visual system has access to high-resolution extra-retinal knowledge of fixational eye motion and uses it to deduce spatial relations. Building on recent advances in gaze-contingent display control, we created a spatial discrimination task in which the stimulus configuration was entirely determined by oculomotor activity. Our results show that humans correctly infer geometrical relations in the absence of spatial information on the retina and accurately combine high-resolution extraretinal monitoring of gaze displacement with retinal signals. These findings reveal a sensory-motor strategy for encoding space, in which fine oculomotor knowledge is used to interpret the fixational input to the retina.
    DOI:  https://doi.org/10.1038/s41467-023-35834-4
  49. Nat Immunol. 2023 Jan 19.
    IL-1α-releasing TH17 cells live long and prosper.
    Joanna R Groom, James E Vince.
      
    DOI:  https://doi.org/10.1038/s41590-022-01412-x
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