bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–05–12
forty-four papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
  2. Shifting my perspective.
  3. The intrinsic substrate specificity of the human tyrosine kinome.
  4. An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
  5. The hidden functional diversity of macrophages.
  6. Protect the periportals.
  7. Rebalancing the aged immune system.
  8. Hacking the immune system could slow ageing - here's how.
  9. Nature of epigenetic aging from a single-cell perspective.
  10. Quantitative profiling of regulatory DNA activity at single-cell resolution.
  11. SASP in peripartum cardiomyopathy and preeclampsia.
  12. Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.
  13. Pretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation.
  14. Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.
  15. Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
  16. Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers.
  17. A nascent riboswitch helix orchestrates robust transcriptional regulation through signal integration.
  18. TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.
  19. Replication competent HIV-guided CRISPR screen identifies antiviral factors including targets of the accessory protein Nef.
  20. DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.
  21. A systematic mutational framework for studying oxidative phosphorylation-related proteins.
  22. Cubic millimetre of brain mapped in spectacular detail.
  23. Reply to: Technical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles for vaccine and therapeutic applications.
  24. Bird flu in US cows: where will it end?
  25. How I fled bombed Aleppo to continue my career in science.
  26. Studying paired patient tissue and blood enables insights into immunotherapy toxicity.
  27. Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer's disease mouse models.
  28. MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation.
  29. CRISPR therapy restores some vision to people with blindness.
  30. FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
  31. Argentina's pioneering nuclear research threatened by huge budget cuts.
  32. Precise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states.
  33. The dream of electronic newspapers becomes a reality - in 1974.
  34. Multiplex profiling of developmental cis-regulatory elements with quantitative single-cell expression reporters.
  35. An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.
  36. Tandem repeat variation of human centromeres.
  37. Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1.
  38. Determinants of mosaic chromosomal alteration fitness.
  39. Decoding cell replicational age from single-cell ATAC-seq data.
  40. Branching out beyond canonical brown adipocyte function.
  41. Mapping genotypes to chromatin accessibility profiles in single cells.
  42. Genetic association of inflammatory marker GlycA with lung function and respiratory diseases.
  43. Students can encourage their grandparents to vaccinate.
  44. Impact of distinct FG nucleoporin repeats on Nup98 self-association.
  1. Nat Commun. 2024 May 10. 15(1): 3982
    Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity.
    Güneş Parlakgül, Song Pang, Leonardo L Artico, Nina Min, Erika Cagampan, Reyna Villa, Renata L S Goncalves, Grace Yankun Lee, C Shan Xu, Gökhan S Hotamışlıgil, Ana Paula Arruda.
      The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.
    DOI:  https://doi.org/10.1038/s41467-024-48272-7
  2. Science. 2024 May 10. 384(6696): 706
    Shifting my perspective.
    Ghazala Rauf.
      
    DOI:  https://doi.org/10.1126/science.adq2323
  3. Nature. 2024 May 08.
    The intrinsic substrate specificity of the human tyrosine kinome.
    Tomer M Yaron-Barir, Brian A Joughin, Emily M Huntsman, Alexander Kerelsky, Daniel M Cizin, Benjamin M Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M Orozco, Christina Schoenherr, Cari Sagum, Mark T Bedford, R Max Wynn, Shih-Chia Tso, David T Chuang, Lei Li, Shawn S-C Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C Frame, Peter V Hornbeck, Lewis C Cantley, Benjamin E Turk, Michael B Yaffe, Jared L Johnson.
      Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07407-y
  4. Nat Commun. 2024 May 07. 15(1): 3793
    An interphase actin wave promotes mitochondrial content mixing and organelle homeostasis.
    Stephen M Coscia, Andrew S Moore, Cameron P Thompson, Christian F Tirrito, E Michael Ostap, Erika L F Holzbaur.
      Across the cell cycle, mitochondrial dynamics are regulated by a cycling wave of actin polymerization/depolymerization. In metaphase, this wave induces actin comet tails on mitochondria that propel these organelles to drive spatial mixing, resulting in their equitable inheritance by daughter cells. In contrast, during interphase the cycling actin wave promotes localized mitochondrial fission. Here, we identify the F-actin nucleator/elongator FMNL1 as a positive regulator of the wave. FMNL1-depleted cells exhibit decreased mitochondrial polarization, decreased mitochondrial oxygen consumption, and increased production of reactive oxygen species. Accompanying these changes is a loss of hetero-fusion of wave-fragmented mitochondria. Thus, we propose that the interphase actin wave maintains mitochondrial homeostasis by promoting mitochondrial content mixing. Finally, we investigate the mechanistic basis for the observation that the wave drives mitochondrial motility in metaphase but mitochondrial fission in interphase. Our data indicate that when the force of actin polymerization is resisted by mitochondrial tethering to microtubules, as in interphase, fission results.
    DOI:  https://doi.org/10.1038/s41467-024-48189-1
  5. Nat Immunol. 2024 May 08.
    The hidden functional diversity of macrophages.
      
    DOI:  https://doi.org/10.1038/s41590-024-01832-x
  6. Nat Rev Immunol. 2024 May 08.
    Protect the periportals.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01042-4
  7. Nat Aging. 2024 May 08.
    Rebalancing the aged immune system.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00637-9
  8. Nature. 2024 May;629(8011): 276-278
    Hacking the immune system could slow ageing - here's how.
    Alison Abbott.
      
    Keywords:  Ageing; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-01274-3
  9. Nat Aging. 2024 May 09.
    Nature of epigenetic aging from a single-cell perspective.
    Andrei E Tarkhov, Thomas Lindstrom-Vautrin, Sirui Zhang, Kejun Ying, Mahdi Moqri, Bohan Zhang, Alexander Tyshkovskiy, Orr Levy, Vadim N Gladyshev.
      Age-related changes in DNA methylation (DNAm) form the basis of the most robust predictors of age-epigenetic clocks-but a clear mechanistic understanding of exactly which aspects of aging are quantified by these clocks is lacking. Here, to clarify the nature of epigenetic aging, we juxtapose the dynamics of tissue and single-cell DNAm in mice. We compare these changes during early development with those observed during adult aging in mice, and corroborate our analyses with a single-cell RNA sequencing analysis within the same multiomics dataset. We show that epigenetic aging involves co-regulated changes as well as a major stochastic component, and this is consistent with transcriptional patterns. We further support the finding of stochastic epigenetic aging by direct tissue and single-cell DNAm analyses and modeling of aging DNAm trajectories with a stochastic process akin to radiocarbon decay. Finally, we describe a single-cell algorithm for the identification of co-regulated and stochastic CpG clusters showing consistent transcriptomic coordination patterns. Together, our analyses increase our understanding of the basis of epigenetic clocks and highlight potential opportunities for targeting aging and evaluating longevity interventions.
    DOI:  https://doi.org/10.1038/s43587-024-00616-0
  10. Nat Methods. 2024 May 09.
    Quantitative profiling of regulatory DNA activity at single-cell resolution.
      
    DOI:  https://doi.org/10.1038/s41592-024-02261-2
  11. Nat Aging. 2024 May 09.
    SASP in peripartum cardiomyopathy and preeclampsia.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-024-00638-8
  12. Nat Commun. 2024 May 08. 15(1): 3860
    Plasma proteome profiling reveals dynamic of cholesterol marker after dual blocker therapy.
    Jiacheng Lyu, Lin Bai, Yumiao Li, Xiaofang Wang, Zeya Xu, Tao Ji, Hua Yang, Zizheng Song, Zhiyu Wang, Yanhong Shang, Lili Ren, Yan Li, Aimin Zang, Youchao Jia, Chen Ding.
      Dual blocker therapy (DBT) has the enhanced antitumor benefits than the monotherapy. Yet, few effective biomarkers are developed to monitor the therapy response. Herein, we investigate the DBT longitudinal plasma proteome profiling including 113 longitudinal samples from 22 patients who received anti-PD1 and anti-CTLA4 DBT therapy. The results show the immune response and cholesterol metabolism are upregulated after the first DBT cycle. Notably, the cholesterol metabolism is activated in the disease non-progressive group (DNP) during the therapy. Correspondingly, the clinical indicator prealbumin (PA), free triiodothyronine (FT3) and triiodothyronine (T3) show significantly positive association with the cholesterol metabolism. Furthermore, by integrating proteome and radiology approach, we observe the high-density lipoprotein partial remodeling are activated in DNP group and identify a candidate biomarker APOC3 that can reflect DBT response. Above, we establish a machine learning model to predict the DBT response and the model performance is validated by an independent cohort with balanced accuracy is 0.96. Thus, the plasma proteome profiling strategy evaluates the alteration of cholesterol metabolism and identifies a panel of biomarkers in DBT.
    DOI:  https://doi.org/10.1038/s41467-024-47835-y
  13. Nat Commun. 2024 May 10. 15(1): 3937
    Pretreatment with IL-15 and IL-18 rescues natural killer cells from granzyme B-mediated apoptosis after cryopreservation.
    Abdulla Berjis, Deeksha Muthumani, Oscar A Aguilar, Oz Pomp, Omar Johnson, Amanda V Finck, Nils W Engel, Linhui Chen, Nicolas Plachta, John Scholler, Lewis L Lanier, Carl H June, Neil C Sheppard.
      Human natural killer (NK) cell-based therapies are under assessment for treating various cancers, but cryopreservation reduces both the recovery and function of NK cells, thereby limiting their therapeutic feasibility. Using cryopreservation protocols optimized for T cells, here we find that ~75% of NK cells die within 24 h post-thaw, with the remaining cells displaying reduced cytotoxicity. Using CRISPR-Cas9 gene editing and confocal microscopy, we find that cryopreserved NK cells largely die via apoptosis initiated by leakage of granzyme B from cytotoxic vesicles. Pretreatment of NK cells with a combination of Interleukins-15 (IL-15) and IL-18 prior to cryopreservation improves NK cell recovery to ~90-100% and enables equal tumour control in a xenograft model of disseminated Raji cell lymphoma compared to non-cryopreserved NK cells. The mechanism of IL-15 and IL-18-induced protection incorporates two mechanisms: a transient reduction in intracellular granzyme B levels via degranulation, and the induction of antiapoptotic genes.
    DOI:  https://doi.org/10.1038/s41467-024-47574-0
  14. Cell Death Differ. 2024 May 08.
    Itaconate protects ferroptotic neurons by alkylating GPx4 post stroke.
    Chao Wei, Zhongnan Xiao, Yanling Zhang, Zhaoli Luo, Dongyang Liu, Liye Hu, Danmin Shen, Meng Liu, Lei Shi, Xiaotong Wang, Ting Lan, Qingqing Dai, Jing Liu, Wen Chen, Yurui Zhang, Qingyu Sun, Weihua Wu, Peipei Wang, Chenguang Zhang, Junchi Hu, Chu Wang, Fei Yang, Qian Li.
      Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH.
    DOI:  https://doi.org/10.1038/s41418-024-01303-8
  15. Nat Commun. 2024 May 04. 15(1): 3767
    Giant organelle vesicles to uncover intracellular membrane mechanics and plasticity.
    Alexandre Santinho, Maxime Carpentier, Julio Lopes Sampaio, Mohyeddine Omrane, Abdou Rachid Thiam.
      Tools for accessing and studying organelles remain underdeveloped. Here, we present a method by which giant organelle vesicles (GOVs) are generated by submitting cells to a hypotonic medium followed by plasma membrane breakage. By this means, GOVs ranging from 3 to over 10 µm become available for micromanipulation. GOVs are made from organelles such as the endoplasmic reticulum, endosomes, lysosomes and mitochondria, or in contact with one another such as giant mitochondria-associated ER membrane vesicles. We measure the mechanical properties of each organelle-derived GOV and find that they have distinct properties. In GOVs procured from Cos7 cells, for example, bending rigidities tend to increase from the endoplasmic reticulum to the plasma membrane. We also found that the mechanical properties of giant endoplasmic reticulum vesicles (GERVs) vary depending on their interactions with other organelles or the metabolic state of the cell. Lastly, we demonstrate GERVs' biochemical activity through their capacity to synthesize triglycerides and assemble lipid droplets. These findings underscore the potential of GOVs as valuable tools for studying the biophysics and biology of organelles.
    DOI:  https://doi.org/10.1038/s41467-024-48086-7
  16. Immunity. 2024 May 06. pii: S1074-7613(24)00219-X. [Epub ahead of print]
    Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers.
    Sheenam Verma, Matthew J Dufort, Tayla M Olsen, Samantha Kimmel, Jasmine C Labuda, Sam Scharffenberger, Andrew T McGuire, Oliver J Harrison.
      Induction of commensal-specific immunity contributes to tissue homeostasis, yet the mechanisms underlying induction of commensal-specific B cells remain poorly understood in part due to a lack of tools to identify these cells. Using phage display, we identified segmented filamentous bacteria (SFB) antigens targeted by serum and intestinal antibodies and generated B cell tetramers to track SFB-specific B cells in gut-associated lymphoid tissues. We revealed a compartmentalized response in SFB-specific B cell activation, with a gradient of immunoglobulin A (IgA), IgG1, and IgG2b isotype production along Peyer's patches contrasted by selective production of IgG2b within mesenteric lymph nodes. V(D)J sequencing and monoclonal antibody generation identified somatic hypermutation driven affinity maturation to SFB antigens under homeostatic conditions. Combining phage display and B cell tetramers will enable investigation of the ontogeny and function of commensal-specific B cell responses in tissue immunity, inflammation, and repair.
    Keywords:  B cell; BCR; IgA; IgG; affinity maturation; commensal; microbiota; phage display; segmented filamentous bacteria; tetramer
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.014
  17. Nat Commun. 2024 May 10. 15(1): 3955
    A nascent riboswitch helix orchestrates robust transcriptional regulation through signal integration.
    Adrien Chauvier, Shiba S Dandpat, Rosa Romero, Nils G Walter.
      Widespread manganese-sensing transcriptional riboswitches effect the dependable gene regulation needed for bacterial manganese homeostasis in changing environments. Riboswitches - like most structured RNAs - are believed to fold co-transcriptionally, subject to both ligand binding and transcription events; yet how these processes are orchestrated for robust regulation is poorly understood. Through a combination of single-molecule and bulk approaches, we discover how a single Mn2+ ion and the transcribing RNA polymerase (RNAP), paused immediately downstream by a DNA template sequence, are coordinated by the bridging switch helix P1.1 in the representative Lactococcus lactis riboswitch. This coordination achieves a heretofore-overlooked semi-docked global conformation of the nascent RNA, P1.1 base pair stabilization, transcription factor NusA ejection, and RNAP pause extension, thereby enforcing transcription readthrough. Our work demonstrates how a central, adaptable RNA helix functions analogous to a molecular fulcrum of a first-class lever system to integrate disparate signals for finely balanced gene expression control.
    DOI:  https://doi.org/10.1038/s41467-024-48409-8
  18. Nat Commun. 2024 May 10. 15(1): 3976
    TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.
    Jun-Kai Ma, Li-Da Su, Lin-Lin Feng, Jing-Lin Li, Li Pan, Qupei Danzeng, Yanwei Li, Tongyao Shang, Xiao-Lin Zhan, Si-Ying Chen, Shibo Ying, Jian-Rao Hu, Xue Qun Chen, Qi Zhang, Tingbo Liang, Xin-Jiang Lu.
      Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.
    DOI:  https://doi.org/10.1038/s41467-024-48328-8
  19. Nat Commun. 2024 May 07. 15(1): 3813
    Replication competent HIV-guided CRISPR screen identifies antiviral factors including targets of the accessory protein Nef.
    Caterina Prelli Bozzo, Alexandre Laliberté, Aurora De Luna, Chiara Pastorio, Kerstin Regensburger, Stefan Krebs, Alexander Graf, Helmut Blum, Meta Volcic, Konstantin M J Sparrer, Frank Kirchhoff.
      Innate antiviral factors are essential for effective defense against viral pathogens. However, the identity of major restriction mechanisms remains elusive. Current approaches to discover antiviral factors usually focus on the initial steps of viral replication and are limited to a single round of infection. Here, we engineered libraries of >1500 replication-competent HIV-1 constructs each expressing a single gRNAs to target >500 cellular genes for virus-driven discovery of antiviral factors. Passaging in CD4+ T cells robustly enriched HIV-1 encoding sgRNAs against GRN, CIITA, EHMT2, CEACAM3, CC2D1B and RHOA by >50-fold. Using an HIV-1 library lacking the accessory nef gene, we identified IFI16 as a Nef target. Functional analyses in cell lines and primary CD4+ T cells support that the HIV-driven CRISPR screen identified restriction factors targeting virus entry, transcription, release and infectivity. Our HIV-guided CRISPR technique enables sensitive discovery of physiologically relevant cellular defense factors throughout the entire viral replication cycle.
    DOI:  https://doi.org/10.1038/s41467-024-48228-x
  20. Proc Natl Acad Sci U S A. 2024 May 14. 121(20): e2400610121
    DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.
    Congcong Tian, Qin Zhang, Jing Jia, Jiaqi Zhou, Ziwei Zhang, Srinivasu Karri, Jiuhang Jiang, Quinn Dickinson, Yuan Yao, Xiaorong Tang, Yuxin Huang, Ting Guo, Ziwei He, Zheng Liu, Yuan Gao, Xinran Yang, Yuchun Wu, Kui Ming Chan, Daoqin Zhang, Junhong Han, Chuanhe Yu, Haiyun Gan.
      Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.
    Keywords:  DNA polymerase δ; Pol32; epigenetic inheritance; histone chaperone; parental histone transfer
    DOI:  https://doi.org/10.1073/pnas.2400610121
  21. Nat Metab. 2024 May 08.
    A systematic mutational framework for studying oxidative phosphorylation-related proteins.
      
    DOI:  https://doi.org/10.1038/s42255-024-01042-7
  22. Nature. 2024 May 09.
    Cubic millimetre of brain mapped in spectacular detail.
    Carissa Wong.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-01387-9
  23. Nat Commun. 2024 May 09. 15(1): 3853
    Reply to: Technical challenges of studying the impact of plasma components on the efficacy of lipid nanoparticles for vaccine and therapeutic applications.
    Kai Liu, Elisa Lázaro-Ibáñez, Michael Lerche, Daniel Lindén, Anna Salvati, Alan Sabirsh.
      
    DOI:  https://doi.org/10.1038/s41467-024-47726-2
  24. Nature. 2024 May 08.
    Bird flu in US cows: where will it end?
    Sara Reardon.
      
    Keywords:  Diseases; Epidemiology; Infection; Virology
    DOI:  https://doi.org/10.1038/d41586-024-01333-9
  25. Nature. 2024 May 08.
    How I fled bombed Aleppo to continue my career in science.
    Benjamin Plackett.
      
    Keywords:  Careers; Funding; Lab life; Politics
    DOI:  https://doi.org/10.1038/d41586-024-01374-0
  26. Nat Med. 2024 May 09.
    Studying paired patient tissue and blood enables insights into immunotherapy toxicity.
      
    DOI:  https://doi.org/10.1038/s41591-024-02900-3
  27. Nat Commun. 2024 May 08. 15(1): 3872
    Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer's disease mouse models.
    Caroline Wasén, Leah C Beauchamp, Julia Vincentini, Shuqi Li, Danielle S LeServe, Christian Gauthier, Juliana R Lopes, Thais G Moreira, Millicent N Ekwudo, Zhuoran Yin, Patrick da Silva, Rajesh K Krishnan, Oleg Butovsky, Laura M Cox, Howard L Weiner.
      The gut microbiota and microglia play critical roles in Alzheimer's disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques.
    DOI:  https://doi.org/10.1038/s41467-024-47683-w
  28. Nat Commun. 2024 May 08. 15(1): 3880
    MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation.
    Raphaël Pantier, Megan Brown, Sicheng Han, Katie Paton, Stephen Meek, Thomas Montavon, Nicholas Shukeir, Toni McHugh, David A Kelly, Tino Hochepied, Claude Libert, Thomas Jenuwein, Tom Burdon, Adrian Bird.
      Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells. Importantly, we find that mouse cellular models are highly atypical as MeCP2 distribution is diffuse in most mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which is a mouse subspecies lacking methylated satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form condensates and its localisation is independent of heterochromatin. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns.
    DOI:  https://doi.org/10.1038/s41467-024-47395-1
  29. Nature. 2024 May 09.
    CRISPR therapy restores some vision to people with blindness.
      
    Keywords:  Gene therapy
    DOI:  https://doi.org/10.1038/d41586-024-01285-0
  30. Nat Commun. 2024 May 07. 15(1): 3805
    FGFR inhibition blocks NF-ĸB-dependent glucose metabolism and confers metabolic vulnerabilities in cholangiocarcinoma.
    Yuanli Zhen, Kai Liu, Lei Shi, Simran Shah, Qin Xu, Haley Ellis, Eranga R Balasooriya, Johannes Kreuzer, Robert Morris, Albert S Baldwin, Dejan Juric, Wilhelm Haas, Nabeel Bardeesy.
      Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.
    DOI:  https://doi.org/10.1038/s41467-024-47514-y
  31. Nature. 2024 May 07.
    Argentina's pioneering nuclear research threatened by huge budget cuts.
    Martín De Ambrosio, Fermín Koop.
      
    Keywords:  Energy; Funding; Government
    DOI:  https://doi.org/10.1038/d41586-024-01283-2
  32. Nat Commun. 2024 May 08. 15(1): 3657
    Precise immunofluorescence canceling for highly multiplexed imaging to capture specific cell states.
    Kosuke Tomimatsu, Takeru Fujii, Ryoma Bise, Kazufumi Hosoda, Yosuke Taniguchi, Hiroshi Ochiai, Hiroaki Ohishi, Kanta Ando, Ryoma Minami, Kaori Tanaka, Taro Tachibana, Seiichi Mori, Akihito Harada, Kazumitsu Maehara, Masao Nagasaki, Seiichi Uchida, Hiroshi Kimura, Masashi Narita, Yasuyuki Ohkawa.
      Cell states are regulated by the response of signaling pathways to receptor ligand-binding and intercellular interactions. High-resolution imaging has been attempted to explore the dynamics of these processes and, recently, multiplexed imaging has profiled cell states by achieving a comprehensive acquisition of spatial protein information from cells. However, the specificity of antibodies is still compromised when visualizing activated signals. Here, we develop Precise Emission Canceling Antibodies (PECAbs) that have cleavable fluorescent labeling. PECAbs enable high-specificity sequential imaging using hundreds of antibodies, allowing for reconstruction of the spatiotemporal dynamics of signaling pathways. Additionally, combining this approach with seq-smFISH can effectively classify cells and identify their signal activation states in human tissue. Overall, the PECAb system can serve as a comprehensive platform for analyzing complex cell processes.
    DOI:  https://doi.org/10.1038/s41467-024-47989-9
  33. Nature. 2024 May 07.
    The dream of electronic newspapers becomes a reality - in 1974.
      
    Keywords:  History; Information technology; Microbiology
    DOI:  https://doi.org/10.1038/d41586-024-01220-3
  34. Nat Methods. 2024 May 09.
    Multiplex profiling of developmental cis-regulatory elements with quantitative single-cell expression reporters.
    Jean-Benoît Lalanne, Samuel G Regalado, Silvia Domcke, Diego Calderon, Beth K Martin, Xiaoyi Li, Tony Li, Chase C Suiter, Choli Lee, Cole Trapnell, Jay Shendure.
      The inability to scalably and precisely measure the activity of developmental cis-regulatory elements (CREs) in multicellular systems is a bottleneck in genomics. Here we develop a dual RNA cassette that decouples the detection and quantification tasks inherent to multiplex single-cell reporter assays. The resulting measurement of reporter expression is accurate over multiple orders of magnitude, with a precision approaching the limit set by Poisson counting noise. Together with RNA barcode stabilization via circularization, these scalable single-cell quantitative expression reporters provide high-contrast readouts, analogous to classic in situ assays but entirely from sequencing. Screening >200 regions of accessible chromatin in a multicellular in vitro model of early mammalian development, we identify 13 (8 previously uncharacterized) autonomous and cell-type-specific developmental CREs. We further demonstrate that chimeric CRE pairs generate cognate two-cell-type activity profiles and assess gain- and loss-of-function multicellular expression phenotypes from CRE variants with perturbed transcription factor binding sites. Single-cell quantitative expression reporters can be applied in developmental and multicellular systems to quantitatively characterize native, perturbed and synthetic CREs at scale, with high sensitivity and at single-cell resolution.
    DOI:  https://doi.org/10.1038/s41592-024-02260-3
  35. Mol Cell. 2024 Apr 30. pii: S1097-2765(24)00325-3. [Epub ahead of print]
    An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.
    Jia Ji, Meng-Ke Cui, Rong Zou, Ming-Zhi Wu, Man-Xi Ge, Jiqiang Li, Zai-Rong Zhang.
      Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure.
    Keywords:  ABCG2; ATP13A1; marginally hydrophobic TMD; membrane protein folding; membrane protein topogenesis; multi-spanning membrane protein; poorly hydrophobic TMD; re-orientation; topology; transmembrane domain
    DOI:  https://doi.org/10.1016/j.molcel.2024.04.010
  36. Nat Rev Genet. 2024 May 08.
    Tandem repeat variation of human centromeres.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41576-024-00741-x
  37. Nat Commun. 2024 May 07. 15(1): 3831
    Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1.
    Kyle Scranton, Scott John, Marina Angelini, Federica Steccanella, Soban Umar, Rui Zhang, Joshua I Goldhaber, Riccardo Olcese, Michela Ottolia.
      The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.
    DOI:  https://doi.org/10.1038/s41467-024-47850-z
  38. Nat Commun. 2024 May 07. 15(1): 3800
    Determinants of mosaic chromosomal alteration fitness.
    Yash Pershad, Taralynn Mack, Hannah Poisner, Yasminka A Jakubek, Adrienne M Stilp, Braxton D Mitchell, Joshua P Lewis, Eric Boerwinkle, Ruth J F Loos, Nathalie Chami, Zhe Wang, Kathleen Barnes, Nathan Pankratz, Myriam Fornage, Susan Redline, Bruce M Psaty, Joshua C Bis, Ali Shojaie, Edwin K Silverman, Michael H Cho, Jeong H Yun, Dawn DeMeo, Daniel Levy, Andrew D Johnson, Rasika A Mathias, Margaret A Taub, Donna Arnett, Kari E North, Laura M Raffield, April P Carson, Margaret F Doyle, Stephen S Rich, Jerome I Rotter, Xiuqing Guo, Nancy J Cox, Dan M Roden, Nora Franceschini, Pinkal Desai, Alex P Reiner, Paul L Auer, Paul A Scheet, Siddhartha Jaiswal, Joshua S Weinstock, Alexander G Bick.
      Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.
    DOI:  https://doi.org/10.1038/s41467-024-48190-8
  39. Nat Biotechnol. 2024 May 09.
    Decoding cell replicational age from single-cell ATAC-seq data.
      
    DOI:  https://doi.org/10.1038/s41587-024-02256-6
  40. Cell Metab. 2024 May 07. pii: S1550-4131(24)00131-1. [Epub ahead of print]36(5): 891-892
    Branching out beyond canonical brown adipocyte function.
    Helaina Von Bank, Judith Simcox.
      Brown adipose tissue has long been functionally characterized as an organ that regulates thermogenesis, body weight set point, and glucose homeostasis. In the May 9, 2024, issue of Cell, Verkerke et al. discover a novel function for brown adipose tissue in processing branched-chain amino acids into antioxidant metabolites that enter the circulation and regulate insulin signaling in the liver.
    DOI:  https://doi.org/10.1016/j.cmet.2024.04.011
  41. Nature. 2024 May 08.
    Mapping genotypes to chromatin accessibility profiles in single cells.
    Franco Izzo, Robert M Myers, Saravanan Ganesan, Levan Mekerishvili, Sanjay Kottapalli, Tamara Prieto, Elliot O Eton, Theo Botella, Andrew J Dunbar, Robert L Bowman, Jesus Sotelo, Catherine Potenski, Eleni P Mimitou, Maximilian Stahl, Sebastian El Ghaity-Beckley, JoAnn Arandela, Ramya Raviram, Daniel C Choi, Ronald Hoffman, Ronan Chaligné, Omar Abdel-Wahab, Peter Smibert, Irene M Ghobrial, Joseph M Scandura, Bridget Marcellino, Ross L Levine, Dan A Landau.
      In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.
    DOI:  https://doi.org/10.1038/s41586-024-07388-y
  42. Nat Commun. 2024 May 04. 15(1): 3751
    Genetic association of inflammatory marker GlycA with lung function and respiratory diseases.
    Yanjun Guo, Quanhong Liu, Zhilin Zheng, Mengxia Qing, Tianci Yao, Bin Wang, Min Zhou, Dongming Wang, Qinmei Ke, Jixuan Ma, Zhilei Shan, Weihong Chen.
      Association of circulating glycoprotein acetyls (GlycA), a systemic inflammation biomarker, with lung function and respiratory diseases remain to be investigated. We examined the genetic correlation, shared genetics, and potential causality of GlycA (N = 115,078) with lung function and respiratory diseases (N = 497,000). GlycA showed significant genetic correlation with FEV1 (rg = -0.14), FVC (rg = -0.18), asthma (rg = 0.21) and COPD (rg = 0.31). We consistently identified ten shared loci (including chr3p21.31 and chr8p23.1) at both SNP and gene level revealing potential shared biological mechanisms involving ubiquitination, immune response, Wnt/β-catenin signaling, cell growth and differentiation in tissues or cells including blood, epithelium, fibroblast, fetal thymus, and fetal intestine. Genetically elevated GlycA was significantly correlated with lung function and asthma susceptibility (354.13 ml decrement of FEV1, 442.28 ml decrement of FVC, and 144% increased risk of asthma per SD increment of GlycA) from MR analyses. Our findings provide insights into biological mechanisms of GlycA in relating to lung function, asthma, and COPD.
    DOI:  https://doi.org/10.1038/s41467-024-47845-w
  43. Nat Aging. 2024 May 09.
    Students can encourage their grandparents to vaccinate.
    Bruno Arpino.
      
    DOI:  https://doi.org/10.1038/s43587-024-00628-w
  44. Nat Commun. 2024 May 07. 15(1): 3797
    Impact of distinct FG nucleoporin repeats on Nup98 self-association.
    Alain Ibáñez de Opakua, Christian F Pantoja, Maria-Sol Cima-Omori, Christian Dienemann, Markus Zweckstetter.
      Nucleoporins rich in phenylalanine/glycine (FG) residues form the permeability barrier within the nuclear pore complex and are implicated in several pathological cellular processes, including oncogenic fusion condensates. The self-association of FG-repeat proteins and interactions between FG-repeats play a critical role in these activities by forming hydrogel-like structures. Here we show that mutation of specific FG repeats of Nup98 can strongly decrease the protein's self-association capabilities. We further present a cryo-electron microscopy structure of a Nup98 peptide fibril with higher stability per residue compared with previous Nup98 fibril structures. The high-resolution structure reveals zipper-like hydrophobic patches which contain a GLFG motif and are less compatible for binding to nuclear transport receptors. The identified distinct molecular properties of different regions of the nucleoporin may contribute to spatial variations in the self-association of FG-repeats, potentially influencing transport processes through the nuclear pore.
    DOI:  https://doi.org/10.1038/s41467-024-48194-4
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