bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–04–17
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Why do naked mole rats live as long as giraffes?
  2. Daily briefing: Time to rethink the scientific CV.
  3. Genetic origins of schizophrenia find common ground.
  4. Mutational clocks tick differently across species.
  5. CellComm infers cellular crosstalk that drives haematopoietic stem and progenitor cell development.
  6. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours.
  7. Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.
  8. BRD2 compartmentalizes the accessible genome.
  9. Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2.
  10. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma.
  11. Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.
  12. Single-cell RNA sequencing coupled to TCR profiling of large granular lymphocyte leukemia T cells.
  13. Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling.
  14. Self-activated adhesion receptor proteins visualized.
  15. Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis.
  16. Inducible and reversible RNA N6-methyladenosine editing.
  17. Using deep learning to predict abdominal age from liver and pancreas magnetic resonance images.
  18. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.
  19. Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα.
  20. Mapping human haematopoietic stem cells from haemogenic endothelium to birth.
  21. KL1 domain of longevity factor klotho mimics the metabolome of cognitive stimulation and enhances cognition in young and aging mice.
  22. Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking.
  23. Reprogrammed tracrRNAs enable repurposing of RNAs as crRNAs and sequence-specific RNA biosensors.
  24. The tethered peptide activation mechanism of adhesion GPCRs.
  25. Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".
  26. Transient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers.
  27. PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity.
  28. SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
  29. Population-scale long-read sequencing uncovers transposable elements associated with gene expression variation and adaptive signatures in Drosophila.
  30. The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation.
  31. Anopheles mosquitoes reveal new principles of 3D genome organization in insects.
  32. Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia.
  33. ComFC mediates transport and handling of single-stranded DNA during natural transformation.
  34. Fungus packs a punch in the gut.
  35. Non-coding RNA LEVER sequestration of PRC2 can mediate long range gene regulation.
  36. Two-step protocol for regeneration of immunocompetent T cells from mouse pluripotent stem cells.
  37. CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling.
  38. Chromosome evolution and the genetic basis of agronomically important traits in greater yam.
  39. Complex regulation of fatty liver disease.
  40. Super-hydration and reduction of manganese oxide minerals at shallow terrestrial depths.
  41. Therapeutic homology-independent targeted integration in retina and liver.
  42. Protection following BNT162b2 booster in adolescents substantially exceeds that of a fresh 2-dose vaccine.
  43. Evaluating human genetic support for hypothesized metabolic disease genes.
  44. Somatic Diversification of Rearranged Antibody Gene Segments by Intra- and Interchromosomal Templated Mutagenesis.
  45. Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.
  46. Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling.
  47. Construction of a two-dimensional artificial antioxidase for nanocatalytic rheumatoid arthritis treatment.
  1. Nature. 2022 Apr 13.
    Why do naked mole rats live as long as giraffes?
      
    Keywords:  Ageing; Genetics; Particle physics
    DOI:  https://doi.org/10.1038/d41586-022-01062-x
  2. Nature. 2022 Apr 12.
    Daily briefing: Time to rethink the scientific CV.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-022-01054-x
  3. Nature. 2022 Apr;604(7906): 433-435
    Genetic origins of schizophrenia find common ground.
    Conrad O Iyegbe, Paul F O'Reilly.
      
    Keywords:  Genetics; Genomics; Schizophrenia
    DOI:  https://doi.org/10.1038/d41586-022-00773-5
  4. Nature. 2022 Apr;604(7906): 435-436
    Mutational clocks tick differently across species.
    Alexander N Gorelick, Kamila Naxerova.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-022-00976-w
  5. Nat Cell Biol. 2022 Apr 12.
    CellComm infers cellular crosstalk that drives haematopoietic stem and progenitor cell development.
    Edroaldo Lummertz da Rocha, Caroline Kubaczka, Wade W Sugden, Mohamad Ali Najia, Ran Jing, Arianna Markel, Zachary C LeBlanc, Rafael Dos Santos Peixoto, Marcelo Falchetti, James J Collins, Trista E North, George Q Daley.
      Intercellular communication orchestrates a multitude of physiologic and pathologic conditions. Algorithms to infer cell-cell communication and predict downstream signalling and regulatory networks are needed to illuminate mechanisms of stem cell differentiation and tissue development. Here, to fill this gap, we developed and applied CellComm to investigate how the aorta-gonad-mesonephros microenvironment dictates haematopoietic stem and progenitor cell emergence. We identified key microenvironmental signals and transcriptional networks that regulate haematopoietic development, including Stat3, Nr0b2, Ybx1 and App, and confirmed their roles using zebrafish, mouse and human models. Notably, CellComm revealed extensive crosstalk among signalling pathways and convergence on common transcriptional regulators, indicating a resilient developmental programme that ensures dynamic adaptation to changes in the embryonic environment. Our work provides an algorithm and data resource for the scientific community.
    DOI:  https://doi.org/10.1038/s41556-022-00884-1
  6. Nature. 2022 Apr 13.
    CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours.
    Rebecca C Larson, Michael C Kann, Stefanie R Bailey, Nicholas J Haradhvala, Paula Montero Llopis, Amanda A Bouffard, Irene Scarfó, Mark B Leick, Korneel Grauwet, Trisha R Berger, Kai Stewart, Praju Vikas Anekal, Max Jan, Julia Joung, Andrea Schmidts, Tamara Ouspenskaia, Travis Law, Aviv Regev, Gad Getz, Marcela V Maus.
      Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies1-6, but it has shown limited efficacy against solid tumours. Solid tumours may have cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy7,8. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.
    DOI:  https://doi.org/10.1038/s41586-022-04585-5
  7. Nat Commun. 2022 Apr 13. 13(1): 1974
    Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.
    Yujun Hao, Baoyu He, Liping Wu, Yamu Li, Chao Wang, Ting Wang, Longci Sun, Yanhua Zhang, Yangyang Zhan, Yiqing Zhao, Sanford Markowitz, Martina Veigl, Ronald A Conlon, Zhenghe Wang.
      PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29585-x
  8. Nat Genet. 2022 Apr;54(4): 481-491
    BRD2 compartmentalizes the accessible genome.
    Liangqi Xie, Peng Dong, Yifeng Qi, Tsung-Han S Hsieh, Brian P English, SeolKyoung Jung, Xingqi Chen, Margherita De Marzio, Rafael Casellas, Howard Y Chang, Bin Zhang, Robert Tjian, Zhe Liu.
      Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.
    DOI:  https://doi.org/10.1038/s41588-022-01044-9
  9. J Exp Med. 2022 May 02. pii: e20210562. [Epub ahead of print]219(5):
    Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2.
    Vijayashree Mysore, Suhail Tahir, Kazuhiro Furuhashi, Jatin Arora, Florencia Rosetti, Xavier Cullere, Pascal Yazbeck, Miroslav Sekulic, Madeleine E Lemieux, Soumya Raychaudhuri, Bruce H Horwitz, Tanya N Mayadas.
      Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2-activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2-activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.
    DOI:  https://doi.org/10.1084/jem.20210562
  10. Nat Commun. 2022 Apr 11. 13(1): 1935
    Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma.
    Jeppe Sejerø Holm, Samuel A Funt, Annie Borch, Kamilla Kjærgaard Munk, Anne-Mette Bjerregaard, James L Reading, Colleen Maher, Ashley Regazzi, Phillip Wong, Hikmat Al-Ahmadie, Gopa Iyer, Tripti Tamhane, Amalie Kai Bentzen, Nana Overgaard Herschend, Susan De Wolf, Alexandra Snyder, Taha Merghoub, Jedd D Wolchok, Morten Nielsen, Jonathan E Rosenberg, Dean F Bajorin, Sine Reker Hadrup.
      CD8+ T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in the number of neoantigen-reactive CD8+ T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8+ T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1+ Ki67+ effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8+ T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.
    DOI:  https://doi.org/10.1038/s41467-022-29342-0
  11. Science. 2022 Apr 14. eabn6583
    Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.
    Michele Gabriele, Hugo B Brandão, Simon Grosse-Holz, Asmita Jha, Gina M Dailey, Claudia Cattoglio, Tsung-Han S Hsieh, Leonid Mirny, Christoph Zechner, Anders S Hansen.
      Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and loop extruding cohesins, but the live dynamics of loop formation and stability remain unknown. Here, we directly visualize chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantify looping dynamics by Bayesian inference. Unexpectedly, the Fbn2 loop is both rare and dynamic, with a looped fraction of ~3-6.5% and a median loop lifetime of ~10-30 min. Our results establish that the Fbn2 TAD is highly dynamic, where ~92% of the time cohesin-extruded loops exist within the TAD without bridging both CTCF boundaries. This suggests that single CTCF boundaries rather than the fully CTCF-CTCF looped state may be the primary regulators of functional interactions.
    DOI:  https://doi.org/10.1126/science.abn6583
  12. Nat Commun. 2022 Apr 11. 13(1): 1982
    Single-cell RNA sequencing coupled to TCR profiling of large granular lymphocyte leukemia T cells.
    Shouguo Gao, Zhijie Wu, Bradley Arnold, Carrie Diamond, Sai Batchu, Valentina Giudice, Lemlem Alemu, Diego Quinones Raffo, Xingmin Feng, Sachiko Kajigaya, John Barrett, Sawa Ito, Neal S Young.
      T-cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease and bone marrow failure syndrome which responds to immunosuppressive therapies. We show single-cell TCR coupled with RNA sequencing of CD3+ T cells from 13 patients, sampled before and after alemtuzumab treatments. Effector memory T cells and loss of T cell receptor (TCR) repertoire diversity are prevalent in T-LGLL. Shared TCRA and TCRB clonotypes are absent. Deregulation of cell survival and apoptosis gene programs, and marked downregulation of apoptosis genes in CD8+ clones, are prominent features of T-LGLL cells. Apoptosis genes are upregulated after alemtuzumab treatment, especially in responders than non-responders; baseline expression levels of apoptosis genes are predictive of hematologic response. Alemtuzumab does not attenuate TCR clonality, and TCR diversity is further skewed after treatment. Inferences made from analysis of single cell data inform understanding of the pathophysiologic mechanisms of clonal expansion and persistence in T-LGLL.
    DOI:  https://doi.org/10.1038/s41467-022-29175-x
  13. Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00448-X. [Epub ahead of print]39(2): 110690
    Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling.
    Jeffrey R Johnson, David C Crosby, Judd F Hultquist, Andrew P Kurland, Prithy Adhikary, Donna Li, John Marlett, Justine Swann, Ruth Hüttenhain, Erik Verschueren, Tasha L Johnson, Billy W Newton, Michael Shales, Viviana A Simon, Pedro Beltrao, Alan D Frankel, Alexander Marson, Jeffery S Cox, Oliver I Fregoso, John A T Young, Nevan J Krogan.
      Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting post-translational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We use mass spectrometry-based proteomics to quantify changes in protein abundance and two PTM types-phosphorylation and ubiquitination-in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis reveals a requirement for Aurora kinase activity in HIV-1 infection and identified putative substrates of a phosphatase that is degraded during infection. Finally, we demonstrate that the HIV-1 Vpr protein inhibits histone H1 ubiquitination, leading to defects in DNA repair.
    Keywords:  CP: Microbiology; CP: Molecular biology; HIV-1; b56; histone h1; phosphorylation; pp2a; proteomics; systems biology; ubiquitination; vif; vpr
    DOI:  https://doi.org/10.1016/j.celrep.2022.110690
  14. Nature. 2022 Apr 13.
    Self-activated adhesion receptor proteins visualized.
    Antony A Boucard.
      
    Keywords:  Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-00972-0
  15. Nat Cell Biol. 2022 Apr 11.
    Genome-wide CRISPR screen identifies PRC2 and KMT2D-COMPASS as regulators of distinct EMT trajectories that contribute differentially to metastasis.
    Yun Zhang, Joana Liu Donaher, Sunny Das, Xin Li, Ferenc Reinhardt, Jordan A Krall, Arthur W Lambert, Prathapan Thiru, Heather R Keys, Mehreen Khan, Matan Hofree, Molly M Wilson, Ozlem Yedier-Bayram, Nathan A Lack, Tamer T Onder, Tugba Bagci-Onder, Michael Tyler, Itay Tirosh, Aviv Regev, Jacqueline A Lees, Robert A Weinberg.
      Epithelial-mesenchymal transition (EMT) programs operate within carcinoma cells, where they generate phenotypes associated with malignant progression. In their various manifestations, EMT programs enable epithelial cells to enter into a series of intermediate states arrayed along the E-M phenotypic spectrum. At present, we lack a coherent understanding of how carcinoma cells control their entrance into and continued residence in these various states, and which of these states favour the process of metastasis. Here we characterize a layer of EMT-regulating machinery that governs E-M plasticity (EMP). This machinery consists of two chromatin-modifying complexes, PRC2 and KMT2D-COMPASS, which operate as critical regulators to maintain a stable epithelial state. Interestingly, loss of these two complexes unlocks two distinct EMT trajectories. Dysfunction of PRC2, but not KMT2D-COMPASS, yields a quasi-mesenchymal state that is associated with highly metastatic capabilities and poor survival of patients with breast cancer, suggesting that great caution should be applied when PRC2 inhibitors are evaluated clinically in certain patient cohorts. These observations identify epigenetic factors that regulate EMP, determine specific intermediate EMT states and, as a direct consequence, govern the metastatic ability of carcinoma cells.
    DOI:  https://doi.org/10.1038/s41556-022-00877-0
  16. Nat Commun. 2022 Apr 12. 13(1): 1958
    Inducible and reversible RNA N6-methyladenosine editing.
    Huaxia Shi, Ying Xu, Na Tian, Ming Yang, Fu-Sen Liang.
      RNA modifications, including N6-methyladenosine (m6A), have been reported to regulate fundamental RNA processes and properties, and directly linked to various human diseases. Methods enabling temporal and transcript/locus-specific editing of specific RNA modifications are essential, but still limited, to dissect the dynamic and context-dependent functions of these epigenetic modifications. Here, we develop a chemically inducible and reversible RNA m6A modification editing platform integrating chemically induced proximity (CIP) and CRISPR methods. We show that m6A editing can be temporally controlled at specific sites of individual RNA transcripts by the addition or removal of the CIP inducer, abscisic acid (ABA), in the system. By incorporating a photo-caged ABA, a light-controlled version of m6A editing platform can be developed. We expect that this platform and strategy can be generally applied to edit other RNA modifications in addition to m6A.
    DOI:  https://doi.org/10.1038/s41467-022-29665-y
  17. Nat Commun. 2022 Apr 13. 13(1): 1979
    Using deep learning to predict abdominal age from liver and pancreas magnetic resonance images.
    Alan Le Goallec, Samuel Diai, Sasha Collin, Jean-Baptiste Prost, Théo Vincent, Chirag J Patel.
      With age, the prevalence of diseases such as fatty liver disease, cirrhosis, and type two diabetes increases. Approaches to both predict abdominal age and identify risk factors for accelerated abdominal age may ultimately lead to advances that will delay the onset of these diseases. We build an abdominal age predictor by training convolutional neural networks to predict abdominal age (or "AbdAge") from 45,552 liver magnetic resonance images [MRIs] and 36,784 pancreas MRIs (R-Squared = 73.3 ± 0.6; mean absolute error = 2.94 ± 0.03 years). Attention maps show that the prediction is driven by both liver and pancreas anatomical features, and surrounding organs and tissue. Abdominal aging is a complex trait, partially heritable (h_g2 = 26.3 ± 1.9%), and associated with 16 genetic loci (e.g. in PLEKHA1 and EFEMP1), biomarkers (e.g body impedance), clinical phenotypes (e.g, chest pain), diseases (e.g. hypertension), environmental (e.g smoking), and socioeconomic (e.g education, income) factors.
    DOI:  https://doi.org/10.1038/s41467-022-29525-9
  18. Nat Commun. 2022 Apr 12. 13(1): 1969
    Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.
    Chao Wang, Li Fan, Rabia R Khawaja, Bangyan Liu, Lihong Zhan, Lay Kodama, Marcus Chin, Yaqiao Li, David Le, Yungui Zhou, Carlo Condello, Lea T Grinberg, William W Seeley, Bruce L Miller, Sue-Ann Mok, Jason E Gestwicki, Ana Maria Cuervo, Wenjie Luo, Li Gan.
      Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.
    DOI:  https://doi.org/10.1038/s41467-022-29552-6
  19. Nat Commun. 2022 Apr 13. 13(1): 1972
    Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα.
    Hyeri Nam, Younghwan Lee, Boil Kim, Ji-Won Lee, Seohyeon Hwang, Hyun-Kyu An, Kyung Min Chung, Youngjin Park, Jihyun Hong, Kyungjin Kim, Eun-Kyoung Kim, Han Kyoung Choe, Seong-Woon Yu.
      Hyperimmunity drives the development of Alzheimer disease (AD). The immune system is under the circadian control, and circadian abnormalities aggravate AD progress. Here, we investigate how an AD-linked mutation deregulates expression of circadian genes and induces cognitive decline using the knock-in (KI) mice heterozygous for presenilin 2 N141I mutation. This mutation causes selective overproduction of clock gene-controlled cytokines through the DNA hypermethylation-mediated repression of REV-ERBα in innate immune cells. The KI/+ mice are vulnerable to otherwise innocuous, mild immune challenges. The antipsychotic chlorpromazine restores the REV-ERBα level by normalizing DNA methylation through the inhibition of PI3K/AKT1 pathway, and prevents the overexcitation of innate immune cells and cognitive decline in KI/+ mice. These results highlight a pathogenic link between this AD mutation and immune cell overactivation through the epigenetic suppression of REV-ERBα.
    DOI:  https://doi.org/10.1038/s41467-022-29653-2
  20. Nature. 2022 Apr 13.
    Mapping human haematopoietic stem cells from haemogenic endothelium to birth.
    Vincenzo Calvanese, Sandra Capellera-Garcia, Feiyang Ma, Iman Fares, Simone Liebscher, Elizabeth S Ng, Sophia Ekstrand, Júlia Aguadé-Gorgorió, Anastasia Vavilina, Diane Lefaudeux, Brian Nadel, Jacky Y Li, Yanling Wang, Lydia K Lee, Reza Ardehali, M Luisa Iruela-Arispe, Matteo Pellegrini, Ed G Stanley, Andrew G Elefanty, Katja Schenke-Layland, Hanna K A Mikkola.
      The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+ distinguishes HSCs from progenitors throughout gestation. In addition to the aorta-gonad-mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+ haemogenic endothelial cells, which arose from an IL33+ALDH1A1+ arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta-gonad-mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.
    DOI:  https://doi.org/10.1038/s41586-022-04571-x
  21. J Neurosci. 2022 Apr 06. pii: JN-RM-2458-21. [Epub ahead of print]
    KL1 domain of longevity factor klotho mimics the metabolome of cognitive stimulation and enhances cognition in young and aging mice.
    Shweta Gupta, Arturo J Moreno, Dan Wang, Julio Leon, Chen Chen, Oliver Hahn, Yan Poon, Kenneth Greenberg, Nathaniel David, Tony Wyss-Coray, Daniel Raftery, Daniel E L Promislow, Dena B Dubal.
      Cognitive deficits are a major biomedical challenge - and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biologic effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus - and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a close metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENTCognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognition. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain - and provide a plausible therapeutic intervention for mimicking these alterations, that in turn, improves cognition in the young and aging brain.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2458-21.2022
  22. Nat Genet. 2022 Apr;54(4): 492-498
    Single-cell analysis of somatic mutations in human bronchial epithelial cells in relation to aging and smoking.
    Zhenqiu Huang, Shixiang Sun, Moonsook Lee, Alexander Y Maslov, Miao Shi, Spencer Waldman, Ava Marsh, Taha Siddiqui, Xiao Dong, Yakov Peter, Ali Sadoughi, Chirag Shah, Kenny Ye, Simon D Spivack, Jan Vijg.
      Although lung cancer risk among smokers is dependent on smoking dose, it remains unknown if this increased risk reflects an increased rate of somatic mutation accumulation in normal lung cells. Here, we applied single-cell whole-genome sequencing of proximal bronchial basal cells from 33 participants aged between 11 and 86 years with smoking histories varying from never-smoking to 116 pack-years. We found an increase in the frequency of single-nucleotide variants and small insertions and deletions with chronological age in never-smokers, with mutation frequencies significantly elevated among smokers. When plotted against smoking pack-years, mutations followed the linear increase in cancer risk until about 23 pack-years, after which no further increase in mutation frequency was observed, pointing toward individual selection for mutation avoidance. Known lung cancer-defined mutation signatures tracked with both age and smoking. No significant enrichment for somatic mutations in lung cancer driver genes was observed.
    DOI:  https://doi.org/10.1038/s41588-022-01035-w
  23. Nat Commun. 2022 Apr 11. 13(1): 1937
    Reprogrammed tracrRNAs enable repurposing of RNAs as crRNAs and sequence-specific RNA biosensors.
    Yang Liu, Filipe Pinto, Xinyi Wan, Zhugen Yang, Shuguang Peng, Mengxi Li, Jonathan M Cooper, Zhen Xie, Christopher E French, Baojun Wang.
      In type II CRISPR systems, the guide RNA (gRNA) comprises a CRISPR RNA (crRNA) and a hybridized trans-acting CRISPR RNA (tracrRNA), both being essential in guided DNA targeting functions. Although tracrRNAs are diverse in sequence and structure across type II CRISPR systems, the programmability of crRNA-tracrRNA hybridization for Cas9 is not fully understood. Here, we reveal the programmability of crRNA-tracrRNA hybridization for Streptococcus pyogenes Cas9, and in doing so, redefine the capabilities of Cas9 proteins and the sources of crRNAs, providing new biosensing applications for type II CRISPR systems. By reprogramming the crRNA-tracrRNA hybridized sequence, we show that engineered crRNA-tracrRNA interactions can not only enable the design of orthogonal cellular computing devices but also facilitate the hijacking of endogenous small RNAs/mRNAs as crRNAs. We subsequently describe how these re-engineered gRNA pairings can be implemented as RNA sensors, capable of monitoring the transcriptional activity of various environment-responsive genomic genes, or detecting SARS-CoV-2 RNA in vitro, as an Atypical gRNA-activated Transcription Halting Alarm (AGATHA) biosensor.
    DOI:  https://doi.org/10.1038/s41467-022-29604-x
  24. Nature. 2022 Apr 13.
    The tethered peptide activation mechanism of adhesion GPCRs.
    Ximena Barros-Álvarez, Robert M Nwokonko, Alexander Vizurraga, Donna Matzov, Feng He, Makaía M Papasergi-Scott, Michael J Robertson, Ouliana Panova, Eliane Hadas Yardeni, Alpay B Seven, Frank E Kwarcinski, Hongyu Su, Maria Claudia Peroto, Justin G Meyerowitz, Moran Shalev-Benami, Gregory G Tall, Georgios Skiniotis.
      Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions1. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface1. Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood2-5. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.
    DOI:  https://doi.org/10.1038/s41586-022-04575-7
  25. Science. 2022 Apr 15. 376(6590): eabn7083
    Comment on "Impact of neurodegenerative diseases on human adult hippocampal neurogenesis".
    Jon I Arellano, Alvaro Duque, Pasko Rakic.
      
    DOI:  https://doi.org/10.1126/science.abn7083
  26. Nat Commun. 2022 Apr 11. 13(1): 1944
    Transient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers.
    ANRS VISCONTI Study Group
      HIV-1 post-treatment controllers are rare individuals controlling HIV-1 infection for years after antiretroviral therapy interruption. Identification of immune correlates of control in post-treatment controllers could aid in designing effective HIV-1 vaccine and remission strategies. Here, we perform comprehensive immunoprofiling of the humoral response to HIV-1 in long-term post-treatment controllers. Global multivariate analyses combining clinico-virological and humoral immune data reveal distinct profiles in post-treatment controllers experiencing transient viremic episodes off therapy compared to those stably aviremic. Virally-exposed post-treatment controllers display stronger HIV-1 humoral responses, and develop more frequently Env-specific memory B cells and cross-neutralizing antibodies. Both are linked to short viremic exposures, which are also accompanied by an increase in blood atypical memory B cells and activated subsets of circulating follicular helper T cells. Still, most humoral immune variables only correlate with Th2-like circulating follicular helper T cells. Thus, post-treatment controllers form a heterogeneous group with two distinct viral behaviours and associated immune signatures. Post-treatment controllers stably aviremic present "silent" humoral profiles, while those virally-exposed develop functionally robust HIV-specific B-cell and antibody responses, which may participate in controlling infection.
    DOI:  https://doi.org/10.1038/s41467-022-29511-1
  27. Nat Commun. 2022 Apr 13. 13(1): 1983
    PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity.
    Caroline Hoffmann, Floriane Noel, Maximilien Grandclaudon, Lucile Massenet-Regad, Paula Michea, Philemon Sirven, Lilith Faucheux, Aurore Surun, Olivier Lantz, Mylene Bohec, Jian Ye, Weihua Guo, Juliette Rochefort, Jerzy Klijanienko, Sylvain Baulande, Charlotte Lecerf, Maud Kamal, Christophe Le Tourneau, Maude Guillot-Delost, Vassili Soumelis.
      Dendritic cells (DC) are traditionally classified according to their ontogeny and their ability to induce T cell response to antigens, however, the phenotypic and functional state of these cells in cancer does not necessarily align to the conventional categories. Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs produce low levels of secreted factors but induce high levels and a broad range of Th cytokines. Secretory DCs bear a single-cell transcriptomic signature indicative of mature migratory LAMP3+ DCs associated with cancer and inflammation. Secretory DCs are linked to good prognosis in head and neck squamous cell carcinoma, and to response to checkpoint blockade in Melanoma. Hence, the functional dichotomy of DCs we describe has both fundamental and translational implications in inflammation and immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-29516-w
  28. Nat Commun. 2022 Apr 12. 13(1): 1968
    SWI/SNF and the histone chaperone Rtt106 drive expression of the Pleiotropic Drug Resistance network genes.
    Vladislav N Nikolov, Dhara Malavia, Takashi Kubota.
      The Pleiotropic Drug Resistance (PDR) network is central to the drug response in fungi, and its overactivation is associated with drug resistance. However, gene regulation of the PDR network is not well understood. Here, we show that the histone chaperone Rtt106 and the chromatin remodeller SWI/SNF control expression of the PDR network genes and confer drug resistance. In Saccharomyces cerevisiae, Rtt106 specifically localises to PDR network gene promoters dependent on transcription factor Pdr3, but not Pdr1, and is essential for Pdr3-mediated basal expression of the PDR network genes, while SWI/SNF is essential for both basal and drug-induced expression. Also in the pathogenic fungus Candida glabrata, Rtt106 and SWI/SNF regulate drug-induced PDR gene expression. Consistently, loss of Rtt106 or SWI/SNF sensitises drug-resistant S. cerevisiae mutants and C. glabrata to antifungal drugs. Since they cooperatively drive PDR network gene expression, Rtt106 and SWI/SNF represent potential therapeutic targets to combat antifungal resistance.
    DOI:  https://doi.org/10.1038/s41467-022-29591-z
  29. Nat Commun. 2022 Apr 12. 13(1): 1948
    Population-scale long-read sequencing uncovers transposable elements associated with gene expression variation and adaptive signatures in Drosophila.
    Gabriel E Rech, Santiago Radío, Sara Guirao-Rico, Laura Aguilera, Vivien Horvath, Llewellyn Green, Hannah Lindstadt, Véronique Jamilloux, Hadi Quesneville, Josefa González.
      High quality reference genomes are crucial to understanding genome function, structure and evolution. The availability of reference genomes has allowed us to start inferring the role of genetic variation in biology, disease, and biodiversity conservation. However, analyses across organisms demonstrate that a single reference genome is not enough to capture the global genetic diversity present in populations. In this work, we generate 32 high-quality reference genomes for the well-known model species D. melanogaster and focus on the identification and analysis of transposable element variation as they are the most common type of structural variant. We show that integrating the genetic variation across natural populations from five climatic regions increases the number of detected insertions by 58%. Moreover, 26% to 57% of the insertions identified using long-reads were missed by short-reads methods. We also identify hundreds of transposable elements associated with gene expression variation and new TE variants likely to contribute to adaptive evolution in this species. Our results highlight the importance of incorporating the genetic variation present in natural populations to genomic studies, which is essential if we are to understand how genomes function and evolve.
    DOI:  https://doi.org/10.1038/s41467-022-29518-8
  30. Nat Commun. 2022 Apr 13. 13(1): 1991
    The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation.
    Tomoya Sakamoto, Kirill Batmanov, Shibiao Wan, Yuanjun Guo, Ling Lai, Rick B Vega, Daniel P Kelly.
      Estrogen-related receptors (ERR) α and γ were shown recently to serve as regulators of cardiac maturation, yet the underlying mechanisms have not been delineated. Herein, we find that ERR signaling is necessary for induction of genes involved in mitochondrial and cardiac-specific contractile processes during human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) differentiation. Genomic interrogation studies demonstrate that ERRγ occupies many cardiomyocyte enhancers/super-enhancers, often co-localizing with the cardiogenic factor GATA4. ERRγ interacts with GATA4 to cooperatively activate transcription of targets involved in cardiomyocyte-specific processes such as contractile function, whereas ERRγ-mediated control of metabolic genes occurs independent of GATA4. Both mechanisms require the transcriptional coregulator PGC-1α. A disease-causing GATA4 mutation is shown to diminish PGC-1α/ERR/GATA4 cooperativity and expression of ERR target genes are downregulated in human heart failure samples suggesting that dysregulation of this circuitry may contribute to congenital and acquired forms of heart failure.
    DOI:  https://doi.org/10.1038/s41467-022-29733-3
  31. Nat Commun. 2022 Apr 12. 13(1): 1960
    Anopheles mosquitoes reveal new principles of 3D genome organization in insects.
    Varvara Lukyanchikova, Miroslav Nuriddinov, Polina Belokopytova, Alena Taskina, Jiangtao Liang, Maarten J M F Reijnders, Livio Ruzzante, Romain Feron, Robert M Waterhouse, Yang Wu, Chunhong Mao, Zhijian Tu, Igor V Sharakhov, Veniamin Fishman.
      Chromosomes are hierarchically folded within cell nuclei into territories, domains and subdomains, but the functional importance and evolutionary dynamics of these hierarchies are poorly defined. Here, we comprehensively profile genome organizations of five Anopheles mosquito species and show how different levels of chromatin architecture influence each other. Patterns observed on Hi-C maps are associated with known cytological structures, epigenetic profiles, and gene expression levels. Evolutionary analysis reveals conservation of chromatin architecture within synteny blocks for tens of millions of years and enrichment of synteny breakpoints in regions with increased genomic insulation. However, in-depth analysis shows a confounding effect of gene density on both insulation and distribution of synteny breakpoints, suggesting limited causal relationship between breakpoints and regions with increased genomic insulation. At the level of individual loci, we identify specific, extremely long-ranged looping interactions, conserved for ~100 million years. We demonstrate that the mechanisms underlying these looping contacts differ from previously described Polycomb-dependent interactions and clustering of active chromatin.
    DOI:  https://doi.org/10.1038/s41467-022-29599-5
  32. Nat Commun. 2022 Apr 11. 13(1): 1981
    Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia.
    Jani Huuhtanen, Dipabarna Bhattacharya, Tapio Lönnberg, Matti Kankainen, Cassandra Kerr, Jason Theodoropoulos, Hanna Rajala, Carmelo Gurnari, Tiina Kasanen, Till Braun, Antonella Teramo, Renato Zambello, Marco Herling, Fumihiro Ishida, Toru Kawakami, Marko Salmi, Thomas Loughran, Jaroslaw P Maciejewski, Harri Lähdesmäki, Tiina Kelkka, Satu Mustjoki.
      T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T cell response to an antigen, the function of the non-leukemic immune system in this response is largely uncharacterized. Here, by utilizing single-cell RNA and T cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes. In addition, T-LGLL clonotypes show more active cell communication than reactive clones with non-leukemic immune cells via costimulatory cell-cell interactions, monocyte-secreted proinflammatory cytokines, and T-LGLL-clone-secreted IFNγ. Besides the leukemic repertoire, the non-leukemic T cell repertoire in T-LGLL is also more mature, cytotoxic, and clonally restricted than in other cancers and autoimmune disorders. Finally, 72% of the leukemic T-LGLL clonotypes share T cell receptor similarities with their non-leukemic repertoire, linking the leukemic and non-leukemic repertoires together via possible common target antigens. Our results provide a rationale to prioritize therapies that target the entire immune repertoire and not only the T-LGLL clonotype.
    DOI:  https://doi.org/10.1038/s41467-022-29173-z
  33. Nat Commun. 2022 Apr 12. 13(1): 1961
    ComFC mediates transport and handling of single-stranded DNA during natural transformation.
    Prashant P Damke, Louisa Celma, Sumedha M Kondekar, Anne Marie Di Guilmi, Stéphanie Marsin, Jordane Dépagne, Xavier Veaute, Pierre Legrand, Hélène Walbott, Julien Vercruyssen, Raphaël Guérois, Sophie Quevillon-Cheruel, J Pablo Radicella.
      The ComFC protein is essential for natural transformation, a process that plays a major role in the spread of antibiotic resistance genes and virulence factors across bacteria. However, its role remains largely unknown. Here, we show that Helicobacter pylori ComFC is involved in DNA transport through the cell membrane, and is required for the handling of the single-stranded DNA once it is delivered into the cytoplasm. The crystal structure of ComFC includes a zinc-finger motif and a putative phosphoribosyl transferase domain, both necessary for the protein's in vivo activity. Furthermore, we show that ComFC is a membrane-associated protein with affinity for single-stranded DNA. Our results suggest that ComFC provides the link between the transport of the transforming DNA into the cytoplasm and its handling by the recombination machinery.
    DOI:  https://doi.org/10.1038/s41467-022-29494-z
  34. Immunity. 2022 Apr 12. pii: S1074-7613(22)00135-2. [Epub ahead of print]55(4): 586-588
    Fungus packs a punch in the gut.
    Daniel H Cho, Gloria B Choi.
      The impact of intestinal fungi on host physiology and their mechanisms of interaction are incompletely understood. In a recent issue of Cell, Leonardi et al. (2022) showed that mucosal fungi induce intestinal Th17 cells to produce IL-22 and IL-17A. IL-22 acts on the gut epithelium to protect barrier integrity, whereas IL-17 acts on IL-17RA+ neurons to enhance sociability.
    DOI:  https://doi.org/10.1016/j.immuni.2022.03.012
  35. Commun Biol. 2022 Apr 11. 5(1): 343
    Non-coding RNA LEVER sequestration of PRC2 can mediate long range gene regulation.
    Wei Wen Teo, Xinang Cao, Chan-Shuo Wu, Hong Kee Tan, Qiling Zhou, Chong Gao, Kim Vanuytsel, Sara S Kumar, George J Murphy, Henry Yang, Li Chai, Daniel G Tenen.
      Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator required for gene silencing during development. Although PRC2 is a well-established RNA-binding complex, the biological function of PRC2-RNA interaction has been controversial. Here, we study the gene-regulatory role of the inhibitory PRC2-RNA interactions. We report a nuclear long non-coding RNA, LEVER, which mapped 236 kb upstream of the β-globin cluster as confirmed by Nanopore sequencing. LEVER RNA interacts with PRC2 in its nascent form, and this prevents the accumulation of the H3K27 repressive histone marks within LEVER locus. Interestingly, the accessible LEVER chromatin, in turn, suppresses the chromatin interactions between the ε-globin locus and β-globin locus control region (LCR), resulting in a repressive effect on ε-globin gene expression. Our findings validate that the nascent RNA-PRC2 interaction inhibits local PRC2 function in situ. More importantly, we demonstrate that such a local process can in turn regulate the expression of neighboring genes.
    DOI:  https://doi.org/10.1038/s42003-022-03250-x
  36. Blood Sci. 2020 Jul;2(3): 79-88
    Two-step protocol for regeneration of immunocompetent T cells from mouse pluripotent stem cells.
    Tongjie Wang, Cui Lv, Fangxiao Hu, Lijuan Liu, Jinyong Wang.
      Numerous efforts have been attempted to regenerate T cells in culture dish from pluripotent stem cells (PSCs). However, in vitro generated T cells exhibited extremely low activity and compromised immunocompetency in vivo. Here, we describe a two-step protocol for regenerating functional T cells using an inducible Runx1-Hoxa9-PSC (iR9-PSCs) line. The procedure mainly includes generation of induced hematopoietic progenitor cells (iHPCs) in vitro, transplantation, and development of functional induced T cells (iT) in vivo via transplantation. The entire induction process in vitro requires 21 days before iHPCs transplantation. The development of mature T cells in vivo takes 4 to 6 weeks post-transplantation. We provide a simple and reproducible approach for functional T cell regeneration from iR9-PSCs for research purpose.
    Keywords:  Induced hematopoietic progenitor cells; Pluripotent stem cells; T cells regeneration; Transplantation
    DOI:  https://doi.org/10.1097/BS9.0000000000000049
  37. Nat Commun. 2022 Apr 13. 13(1): 1989
    CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling.
    Caojie Liu, Qiuchan Xiong, Qiwen Li, Weimin Lin, Shuang Jiang, Danting Zhang, Yuan Wang, Xiaobo Duan, Ping Gong, Ning Kang.
      Chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent eukaryotic chromatin remodeling enzyme, is essential for the development of organs. The mutation of CHD7 is the main cause of CHARGE syndrome, but its function and mechanism in skeletal system remain unclear. Here, we show conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and preosteoblasts leads to a pathological phenotype manifested as low bone mass and severely high marrow adiposity. Mechanistically, we identify enhancement of the peroxisome proliferator-activated receptor (PPAR) signaling in Chd7-deficient MSCs. Loss of Chd7 reduces the restriction of PPAR-γ and then PPAR-γ associates with trimethylated histone H3 at lysine 4 (H3K4me3), which subsequently activates the transcription of downstream adipogenic genes and disrupts the balance between osteogenic and adipogenic differentiation. Our data illustrate the pathological manifestations of Chd7 mutation in MSCs and reveal an epigenetic mechanism in skeletal health and diseases.
    DOI:  https://doi.org/10.1038/s41467-022-29633-6
  38. Nat Commun. 2022 Apr 14. 13(1): 2001
    Chromosome evolution and the genetic basis of agronomically important traits in greater yam.
    Jessen V Bredeson, Jessica B Lyons, Ibukun O Oniyinde, Nneka R Okereke, Olufisayo Kolade, Ikenna Nnabue, Christian O Nwadili, Eva Hřibová, Matthew Parker, Jeremiah Nwogha, Shengqiang Shu, Joseph Carlson, Robert Kariba, Samuel Muthemba, Katarzyna Knop, Geoffrey J Barton, Anna V Sherwood, Antonio Lopez-Montes, Robert Asiedu, Ramni Jamnadass, Alice Muchugi, David Goodstein, Chiedozie N Egesi, Jonathan Featherston, Asrat Asfaw, Gordon G Simpson, Jaroslav Doležel, Prasad S Hendre, Allen Van Deynze, Pullikanti Lava Kumar, Jude E Obidiegwu, Ranjana Bhattacharjee, Daniel S Rokhsar.
      The nutrient-rich tubers of the greater yam, Dioscorea alata L., provide food and income security for millions of people around the world. Despite its global importance, however, greater yam remains an orphan crop. Here, we address this resource gap by presenting a highly contiguous chromosome-scale genome assembly of D. alata combined with a dense genetic map derived from African breeding populations. The genome sequence reveals an ancient allotetraploidization in the Dioscorea lineage, followed by extensive genome-wide reorganization. Using the genomic tools, we find quantitative trait loci for resistance to anthracnose, a damaging fungal pathogen of yam, and several tuber quality traits. Genomic analysis of breeding lines reveals both extensive inbreeding as well as regions of extensive heterozygosity that may represent interspecific introgression during domestication. These tools and insights will enable yam breeders to unlock the potential of this staple crop and take full advantage of its adaptability to varied environments.
    DOI:  https://doi.org/10.1038/s41467-022-29114-w
  39. Science. 2022 Apr 15. 376(6590): 247-248
    Complex regulation of fatty liver disease.
    Henry N Ginsberg, Arya Mani.
      Hepatic lipogenesis is fine-tuned by mechanistic target of rapamycin (mTOR) signaling.
    DOI:  https://doi.org/10.1126/science.abp8276
  40. Nat Commun. 2022 Apr 11. 13(1): 1942
    Super-hydration and reduction of manganese oxide minerals at shallow terrestrial depths.
    Seohee Yun, Huijeong Hwang, Gilchan Hwang, Yeongkyoo Kim, Douglas Blom, Thomas Vogt, Jeffrey E Post, Tae-Yeol Jeon, Tae Joo Shin, Dong-Zhou Zhang, Hiroyuki Kagi, Yongjae Lee.
      Manganese oxides are ubiquitous marine minerals which are redox sensitive. As major components of manganese nodules found on the ocean floor, birnessite and buserite have been known to be two distinct water-containing minerals with manganese octahedral interlayer separations of ~7 Å and ~10 Å, respectively. We show here that buserite is a super-hydrated birnessite formed near 5 km depth conditions. As one of the most hydrous minerals containing ca. 34.5 wt. % water, super-hydrated birnessite, i.e., buserite, remains stable up to ca. 70 km depth conditions, where it transforms into manganite by releasing ca. 24.3 wt. % water. Subsequent transformations to hausmannite and pyrochroite occur near 100 km and 120 km depths, respectively, concomitant with a progressive reduction of Mn4+ to Mn2+. Our work forwards an abiotic geochemical cycle of manganese minerals in subduction and/or other aqueous terrestrial environments, with implications for water storage and cycling, and the redox capacity of the region.
    DOI:  https://doi.org/10.1038/s41467-022-29328-y
  41. Nat Commun. 2022 Apr 12. 13(1): 1963
    Therapeutic homology-independent targeted integration in retina and liver.
    Patrizia Tornabene, Rita Ferla, Manel Llado-Santaeularia, Miriam Centrulo, Margherita Dell'Anno, Federica Esposito, Elena Marrocco, Emanuela Pone, Renato Minopoli, Carolina Iodice, Edoardo Nusco, Settimio Rossi, Hristiana Lyubenova, Anna Manfredi, Lucio Di Filippo, Antonella Iuliano, Annalaura Torella, Giulio Piluso, Francesco Musacchia, Enrico Maria Surace, Davide Cacchiarelli, Vincenzo Nigro, Alberto Auricchio.
      Challenges to the widespread application of gene therapy with adeno-associated viral (AAV) vectors include dominant conditions due to gain-of-function mutations which require allele-specific knockout, as well as long-term transgene expression from proliferating tissues, which is hampered by AAV DNA episomal status. To overcome these challenges, we used CRISPR/Cas9-mediated homology-independent targeted integration (HITI) in retina and liver as paradigmatic target tissues. We show that AAV-HITI targets photoreceptors of both mouse and pig retina, and this results in significant improvements to retinal morphology and function in mice with autosomal dominant retinitis pigmentosa. In addition, we show that neonatal systemic AAV-HITI delivery achieves stable liver transgene expression and phenotypic improvement in a mouse model of a severe lysosomal storage disease. We also show that HITI applications predominantly result in on-target editing. These results lay the groundwork for the application of AAV-HITI for the treatment of diseases affecting various organs.
    DOI:  https://doi.org/10.1038/s41467-022-29550-8
  42. Nat Commun. 2022 Apr 13. 13(1): 1971
    Protection following BNT162b2 booster in adolescents substantially exceeds that of a fresh 2-dose vaccine.
    Ofra Amir, Yair Goldberg, Micha Mandel, Yinon M Bar-On, Omri Bodenheimer, Nachman Ash, Sharon Alroy-Preis, Amit Huppert, Ron Milo.
      Israel began administering a BNT162b2 booster dose to restore protection following the waning of the 2-dose vaccine. Biological studies have shown that a "fresh" booster dose leads to increased antibody levels compared to a fresh 2-dose vaccine, which may suggest increased effectiveness. To compare the real-world effectiveness of a fresh (up to 60 days) booster dose with that of a fresh 2-dose vaccine, we took advantage of a quasi-experimental study that compares populations that were eligible to receive the vaccine at different times due to age-dependent policies. Specifically, we compared the confirmed infection rates in adolescents aged 12-14 (215,653 individuals) who received the 2-dose vaccine and in adolescents aged 16-18 (103,454 individuals) who received the booster dose. Our analysis shows that the confirmed infection rate was lower by a factor of 3.7 (95% CI: 2.7 to 5.2) in the booster group.
    DOI:  https://doi.org/10.1038/s41467-022-29578-w
  43. Cell Metab. 2022 Apr 09. pii: S1550-4131(22)00125-5. [Epub ahead of print]
    Evaluating human genetic support for hypothesized metabolic disease genes.
    Peter Dornbos, Preeti Singh, Dong-Keun Jang, Anubha Mahajan, Sudha B Biddinger, Jerome I Rotter, Mark I McCarthy, Jason Flannick.
      We investigate the extent to which human genetic data are incorporated into studies that hypothesize novel links between genes and metabolic disease. To lower the barriers to using genetic data, we present an approach to enable researchers to evaluate human genetic support for experimentally determined hypotheses.
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.011
  44. J Immunol. 2022 Apr 13. pii: ji2100434. [Epub ahead of print]
    Somatic Diversification of Rearranged Antibody Gene Segments by Intra- and Interchromosomal Templated Mutagenesis.
    Gordon A Dale, Daniel J Wilkins, Jordan Rowley, Christopher D Scharer, Christopher M Tipton, Jennifer Hom, Jeremy M Boss, Victor Corces, Ignacio Sanz, Joshy Jacob.
      The ability of the humoral immune system to generate Abs capable of specifically binding a myriad of Ags is critically dependent on the somatic hypermutation program. This program induces both templated mutations (i.e., gene conversion) and untemplated mutations. In humans, somatic hypermutation is widely believed to result in untemplated point mutations. In this study, we demonstrate detection of large-scale templated events that occur in human memory B cells and circulating plasmablasts. We find that such mutations are templated intrachromosomally from IGHV genes and interchromosomally from IGHV pseudogenes as well as other homologous regions unrelated to IGHV genes. These same donor regions are used in multiple individuals, and they predominantly originate from chromosomes 14, 15, and 16. In addition, we find that exogenous sequences placed at the IgH locus, such as LAIR1, undergo templated mutagenesis and that homology appears to be the major determinant for donor choice. Furthermore, we find that donor tracts originate from areas in proximity with open chromatin, which are transcriptionally active, and are found in spatial proximity with the IgH locus during the germinal center reaction. These donor sequences are inserted into the Ig gene segment in association with overlapping activation-induced cytidine deaminase hotspots. Taken together, these studies suggest that diversity generated during the germinal center response is driven by untemplated point mutations as well as templated mutagenesis using local and distant regions of the genome.
    DOI:  https://doi.org/10.4049/jimmunol.2100434
  45. Mol Cell. 2022 Apr 07. pii: S1097-2765(22)00264-7. [Epub ahead of print]
    Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.
    Xue Gao, Yijie Liu, Yuancheng Li, Hao Fan, Rong Wu, Rukang Zhang, Brandon Faubert, Yu-Ying He, Marc B Bissonnette, Siyuan Xia, Dong Chen, Hui Mao, Titus J Boggon, Jing Chen.
      Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E. Intracellular Lyso-PAF promotes p21-activated kinase 2 (PAK2) activation by binding to its catalytic domain and altering ATP kinetics, while PAK2 significantly contributes to S338-phosphorylation of RAF1 in addition to PAK1. Furthermore, the PLA2G7-PAK2 axis is also required for full activation of RAF1 in cells stimulated by epidermal growth factor (EGF) or cancer cells expressing mutant KRAS. Thus, PLA2G7 and Lyso-PAF exhibit intracellular signaling functions as key elements of RAS-RAF1 signaling.
    Keywords:  BRAF-V600E; ERK; Lyso-PAF; MEK; RAF1; RAS; p21-activated kinase 2 (PAK2); phospholipase A2 group VII (PLA2G7); phospholipases A2 (PLA2s); platelet-activating factor (PAF)
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.026
  46. Nat Commun. 2022 Apr 12. 13(1): 1952
    Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling.
    Jolanta Chmielowiec, Wojciech J Szlachcic, Diane Yang, Marissa A Scavuzzo, Katrina Wamble, Alejandro Sarrion-Perdigones, Omaima M Sabek, Koen J T Venken, Malgorzata Borowiak.
      In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment's role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit the BMP pathway during β-cell maturation. Interestingly, we also identify the endothelial-derived Endocan as a SST+ cell promoting factor. Overall, our study shows that the pancreatic microenvironment-derived factors can mimic in vivo conditions in an in vitro system to generate bona fide β-cells for translational applications.
    DOI:  https://doi.org/10.1038/s41467-022-29646-1
  47. Nat Commun. 2022 Apr 13. 13(1): 1988
    Construction of a two-dimensional artificial antioxidase for nanocatalytic rheumatoid arthritis treatment.
    Bowen Yang, Heliang Yao, Jiacai Yang, Chang Chen, Jianlin Shi.
      Constructing nanomaterials mimicking the coordination environments of natural enzymes may achieve biomimetic catalysis. Here we construct a two-dimensional (2D) metal-organic framework (MOF) nanosheet catalyst as an artificial antioxidase for nanocatalytic rheumatoid arthritis treatment. The 2D MOF periodically assembles numbers of manganese porphyrin molecules, which has a metal coordination geometry analogous to those of two typical antioxidases, human mitochondrial manganese superoxide dismutase (Mn-SOD) and human erythrocyte catalase. The zinc atoms of the 2D MOF regulate the metal-centered redox potential of coordinated manganese porphyrin ligand, endowing the nanosheet with both SOD- and catalase-like activities. Cellular experiments show unique anti-inflammatory and pro-biomineralization performances of the 2D MOF, while in vivo animal model further demonstrates its desirable antiarthritic efficacy. It is expected that such a nanocatalytic antioxidation concept may provide feasible approaches to future anti-inflammatory treatments.
    DOI:  https://doi.org/10.1038/s41467-022-29735-1
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