bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–07–21
thirty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Chromatin state and BACH2 control TH17 cell functional heterogeneity.
  2. A humanized mouse that mounts specific and mature antibody and autoantibody responses.
  3. Daily briefing: Blocking an inflammation protein lets mice live longer.
  4. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
  5. Mice live longer when inflammation-boosting protein is blocked.
  6. Understanding X chromosome loss.
  7. Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
  8. Can H5N1 spread through cow sneezes? Experiment offers clues.
  9. The death forecast: how weather affects human mortality.
  10. Cutting Edge: Hepatic Stellate Cells Drive the Phenotype of Monocyte-derived Macrophages to Regulate Liver Fibrosis in Metabolic Dysfunction-associated Steatohepatitis.
  11. Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
  12. BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells.
  13. Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
  14. Adipose glutaminolysis resurfaces in metabolic disease.
  15. Found: the hidden link between star-forming molecular clouds.
  16. Kdm4a is an activity downregulated barrier to generate engrams for memory separation.
  17. Competition between two HUSH complexes orchestrates the immune response to retroelement invasion.
  18. Inflammasomes at the Foundation of Inflammatory Cell Death Complexes.
  19. Position-dependent function of human sequence-specific transcription factors.
  20. Symbolic recording of signalling and cis-regulatory element activity to DNA.
  21. TracrRNA reprogramming enables direct PAM-independent detection of RNA with diverse DNA-targeting Cas12 nucleases.
  22. PTPN2 deficiency: Amping up JAK/STAT.
  23. Divergent evolution of male-determining loci on proto-Y chromosomes of the housefly.
  24. From periphery to center stage: 50 years of advancements in innate immunity.
  25. MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data.
  26. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
  27. Measuring nascent transcription in single cells.
  28. Rapid meiotic prophase chromosome movements in Arabidopsis thaliana are linked to essential reorganization at the nuclear envelope.
  29. SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
  30. Inaccurate viral prediction leads to overestimated diversity of the archaeal virome in the human gut.
  31. What happens to the brain during pregnancy?
  32. Advancements in pathogen immunity and signaling.
  1. Nat Immunol. 2024 Jul 17.
    Chromatin state and BACH2 control TH17 cell functional heterogeneity.
      
    DOI:  https://doi.org/10.1038/s41590-024-01904-y
  2. Nat Immunol. 2024 Jul 18.
    A humanized mouse that mounts specific and mature antibody and autoantibody responses.
      
    DOI:  https://doi.org/10.1038/s41590-024-01908-8
  3. Nature. 2024 Jul 18.
    Daily briefing: Blocking an inflammation protein lets mice live longer.
    Katrina Krämer.
      
    DOI:  https://doi.org/10.1038/d41586-024-02367-9
  4. Nat Commun. 2024 Jul 16. 15(1): 5956
    PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
    Mahdi Moqri, Andrea Cipriano, Daniel J Simpson, Sajede Rasouli, Tara Murty, Tineke Anna de Jong, Daniel Nachun, Guilherme de Sena Brandine, Kejun Ying, Andrei Tarkhov, Karolina A Aberg, Edwin van den Oord, Wanding Zhou, Andrew Smith, Crystal Mackall, Vadim N Gladyshev, Steve Horvath, Michael P Snyder, Vittorio Sebastiano.
      DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.
    DOI:  https://doi.org/10.1038/s41467-024-50098-2
  5. Nature. 2024 Jul 17.
    Mice live longer when inflammation-boosting protein is blocked.
    Heidi Ledford.
      
    Keywords:  Ageing; Immunology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02298-5
  6. Nat Genet. 2024 Jul;56(7): 1327
    Understanding X chromosome loss.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-024-01846-z
  7. Nat Commun. 2024 Jul 16. 15(1): 5980
    Metabolic imaging across scales reveals distinct prostate cancer phenotypes.
    Nikita Sushentsev, Gregory Hamm, Lucy Flint, Daniel Birtles, Aleksandr Zakirov, Jack Richings, Stephanie Ling, Jennifer Y Tan, Mary A McLean, Vinay Ayyappan, Ines Horvat Menih, Cara Brodie, Jodi L Miller, Ian G Mills, Vincent J Gnanapragasam, Anne Y Warren, Simon T Barry, Richard J A Goodwin, Tristan Barrett, Ferdia A Gallagher.
      Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.
    DOI:  https://doi.org/10.1038/s41467-024-50362-5
  8. Nature. 2024 Jul 16.
    Can H5N1 spread through cow sneezes? Experiment offers clues.
    Smriti Mallapaty.
      
    Keywords:  Infection
    DOI:  https://doi.org/10.1038/d41586-024-02322-8
  9. Nature. 2024 Jul 16.
    The death forecast: how weather affects human mortality.
      
    Keywords:  History; Medical research; Physics
    DOI:  https://doi.org/10.1038/d41586-024-02230-x
  10. J Immunol. 2024 Aug 01. 213(3): 251-256
    Cutting Edge: Hepatic Stellate Cells Drive the Phenotype of Monocyte-derived Macrophages to Regulate Liver Fibrosis in Metabolic Dysfunction-associated Steatohepatitis.
    Mandy M Chan, Li He, Brian N Finck, Joel D Schilling, Sabine Daemen.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by infiltration of monocyte-derived macrophages (MdMs) into the liver; however, the function of these macrophages is largely unknown. We previously demonstrated that a population of MdMs, referred to as hepatic lipid-associated macrophages (LAMs), assemble into aggregates termed hepatic crown-like structures in areas of liver fibrosis. Intriguingly, decreasing MdM recruitment resulted in increased liver fibrosis, suggesting that LAMs contribute to antifibrotic pathways in MASH. In this study, we determined that hepatic crown-like structures are characterized by intimate interactions between activated hepatic stellate cells (HSCs) and macrophages in a collagen matrix in a mouse model of MASH. MASH macrophages displayed collagen-degrading capacities, and HSCs derived from MASH livers promoted expression of LAM marker genes and acquisition of a collagen-degrading phenotype in naive macrophages. These data suggest that crosstalk between HSCs and macrophages may contribute to collagen degradation MASH.
    DOI:  https://doi.org/10.4049/jimmunol.2300847
  11. Nat Commun. 2024 Jul 18. 15(1): 6067
    Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.
    Marvin Hering, Alaa Madi, Roger Sandhoff, Sicong Ma, Jingxia Wu, Alessa Mieg, Karsten Richter, Kerstin Mohr, Nora Knabe, Diana Stichling, Gernot Poschet, Felix Bestvater, Larissa Frank, Jochen Utikal, Viktor Umansky, Guoliang Cui.
      After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.
    DOI:  https://doi.org/10.1038/s41467-024-50341-w
  12. Nat Immunol. 2024 Jul 15.
    BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells.
    Pratiksha I Thakore, Alexandra Schnell, Linglin Huang, Maryann Zhao, Yu Hou, Elena Christian, Sarah Zaghouani, Chao Wang, Vasundhara Singh, Anvita Singaraju, Rajesh Kumar Krishnan, Deneen Kozoriz, Sai Ma, Venkat Sankar, Samuele Notarbartolo, Jason D Buenrostro, Federica Sallusto, Nikolaos A Patsopoulos, Orit Rozenblatt-Rosen, Vijay K Kuchroo, Aviv Regev.
      Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.
    DOI:  https://doi.org/10.1038/s41590-024-01901-1
  13. Sci Immunol. 2024 Jul 19. 9(97): eadl1903
    Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity.
    Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N J McKenzie, Mark S Cragg, Matthew Hoare, David R Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y F Halim.
      Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adl1903
  14. Nat Metab. 2024 Jul 15.
    Adipose glutaminolysis resurfaces in metabolic disease.
    John A Haley, David A Guertin.
      
    DOI:  https://doi.org/10.1038/s42255-024-01084-x
  15. Nature. 2024 Jul 19.
    Found: the hidden link between star-forming molecular clouds.
      
    Keywords:  Astronomy and astrophysics
    DOI:  https://doi.org/10.1038/d41586-024-02266-z
  16. Nat Commun. 2024 Jul 13. 15(1): 5887
    Kdm4a is an activity downregulated barrier to generate engrams for memory separation.
    Xiuxian Guo, Pengfei Hong, Songhai Xiong, Yuze Yan, Hong Xie, Ji-Song Guan.
      Memory engrams are a subset of learning activated neurons critical for memory recall, consolidation, extinction and separation. While the transcriptional profile of engrams after learning suggests profound neural changes underlying plasticity and memory formation, little is known about how memory engrams are selected and allocated. As epigenetic factors suppress memory formation, we developed a CRISPR screening in the hippocampus to search for factors controlling engram formation. We identified histone lysine-specific demethylase 4a (Kdm4a) as a negative regulator for engram formation. Kdm4a is downregulated after neural activation and controls the volume of mossy fiber boutons. Mechanistically, Kdm4a anchors to the exonic region of Trpm7 gene loci, causing the stalling of nascent RNAs and allowing burst transcription of Trpm7 upon the dismissal of Kdm4a. Furthermore, the YTH domain containing protein 2 (Ythdc2) recruits Kdm4a to the Trpm7 gene and stabilizes nascent RNAs. Reducing the expression of Kdm4a in the hippocampus via genetic manipulation or artificial neural activation facilitated the ability of pattern separation in rodents. Our work indicates that Kdm4a is a negative regulator of engram formation and suggests a priming state to generate a separate memory.
    DOI:  https://doi.org/10.1038/s41467-024-50218-y
  17. Mol Cell. 2024 Jul 06. pii: S1097-2765(24)00527-6. [Epub ahead of print]
    Competition between two HUSH complexes orchestrates the immune response to retroelement invasion.
    Joshua Miguel C Danac, Rachael E Matthews, Akhila Gungi, Chuyan Qin, Harriet Parsons, Robin Antrobus, Richard T Timms, Iva A Tchasovnikarova.
      The human silencing hub (HUSH) preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here, we resolve this paradox by characterizing a second HUSH complex that shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.
    Keywords:  HUSH; HUSH2; IRF2; LINE-1; chromatin; epigenetics; immune response; interferon; retroelement; transposable elements
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.020
  18. J Immunol. 2024 Aug 01. 213(3): 247-249
    Inflammasomes at the Foundation of Inflammatory Cell Death Complexes.
    Rebecca E Tweedell, Thirumala-Devi Kanneganti.
      
    DOI:  https://doi.org/10.4049/jimmunol.2400288
  19. Nature. 2024 Jul 17.
    Position-dependent function of human sequence-specific transcription factors.
    Sascha H Duttke, Carlos Guzman, Max Chang, Nathaniel P Delos Santos, Bayley R McDonald, Jialei Xie, Aaron F Carlin, Sven Heinz, Christopher Benner.
      Patterns of transcriptional activity are encoded in our genome through regulatory elements such as promoters or enhancers that, paradoxically, contain similar assortments of sequence-specific transcription factor (TF) binding sites1-3. Knowledge of how these sequence motifs encode multiple, often overlapping, gene expression programs is central to understanding gene regulation and how mutations in non-coding DNA manifest in disease4,5. Here, by studying gene regulation from the perspective of individual transcription start sites (TSSs), using natural genetic variation, perturbation of endogenous TF protein levels and massively parallel analysis of natural and synthetic regulatory elements, we show that the effect of TF binding on transcription initiation is position dependent. Analysing TF-binding-site occurrences relative to the TSS, we identified several motifs with highly preferential positioning. We show that these patterns are a combination of a TF's distinct functional profiles-many TFs, including canonical activators such as NRF1, NFY and Sp1, activate or repress transcription initiation depending on their precise position relative to the TSS. As such, TFs and their spacing collectively guide the site and frequency of transcription initiation. More broadly, these findings reveal how similar assortments of TF binding sites can generate distinct gene regulatory outcomes depending on their spatial configuration and how DNA sequence polymorphisms may contribute to transcription variation and disease and underscore a critical role for TSS data in decoding the regulatory information of our genome.
    DOI:  https://doi.org/10.1038/s41586-024-07662-z
  20. Nature. 2024 Jul 17.
    Symbolic recording of signalling and cis-regulatory element activity to DNA.
    Wei Chen, Junhong Choi, Xiaoyi Li, Jenny F Nathans, Beth Martin, Wei Yang, Nobuhiko Hamazaki, Chengxiang Qiu, Jean-Benoît Lalanne, Samuel Regalado, Haedong Kim, Vikram Agarwal, Eva Nichols, Anh Leith, Choli Lee, Jay Shendure.
      Measurements of gene expression or signal transduction activity are conventionally performed using methods that require either the destruction or live imaging of a biological sample within the timeframe of interest. Here we demonstrate an alternative paradigm in which such biological activities are stably recorded to the genome. Enhancer-driven genomic recording of transcriptional activity in multiplex (ENGRAM) is based on the signal-dependent production of prime editing guide RNAs that mediate the insertion of signal-specific barcodes (symbols) into a genomically encoded recording unit. We show how this strategy can be used for multiplex recording of the cell-type-specific activities of dozens to hundreds of cis-regulatory elements with high fidelity, sensitivity and reproducibility. Leveraging signal transduction pathway-responsive cis-regulatory elements, we also demonstrate time- and concentration-dependent genomic recording of WNT, NF-κB and Tet-On activities. By coupling ENGRAM to sequential genome editing via DNA Typewriter1, we stably record information about the temporal dynamics of two orthogonal signalling pathways to genomic DNA. Finally we apply ENGRAM to integratively record the transient activity of nearly 100 transcription factor consensus motifs across daily windows spanning the differentiation of mouse embryonic stem cells into gastruloids, an in vitro model of early mammalian development. Although these are proof-of-concept experiments and much work remains to fully realize the possibilities, the symbolic recording of biological signals or states within cells, to the genome and over time, has broad potential to complement contemporary paradigms for how we make measurements in biological systems.
    DOI:  https://doi.org/10.1038/s41586-024-07706-4
  21. Nat Commun. 2024 Jul 13. 15(1): 5909
    TracrRNA reprogramming enables direct PAM-independent detection of RNA with diverse DNA-targeting Cas12 nucleases.
    Chunlei Jiao, Natalia L Peeck, Jiaqi Yu, Mohammad Ghaem Maghami, Sarah Kono, Daphne Collias, Sandra L Martinez Diaz, Rachael Larose, Chase L Beisel.
      Many CRISPR-Cas immune systems generate guide (g)RNAs using trans-activating CRISPR RNAs (tracrRNAs). Recent work revealed that Cas9 tracrRNAs could be reprogrammed to convert any RNA-of-interest into a gRNA, linking the RNA's presence to Cas9-mediated cleavage of double-stranded (ds)DNA. Here, we reprogram tracrRNAs from diverse Cas12 nucleases, linking the presence of an RNA-of-interest to dsDNA cleavage and subsequent collateral single-stranded DNA cleavage-all without the RNA necessarily encoding a protospacer-adjacent motif (PAM). After elucidating nuclease-specific design rules, we demonstrate PAM-independent RNA detection with Cas12b, Cas12e, and Cas12f nucleases. Furthermore, rationally truncating the dsDNA target boosts collateral cleavage activity, while the absence of a gRNA reduces background collateral activity and enhances sensitivity. Finally, we apply this platform to detect 16 S rRNA sequences from five different bacterial pathogens using a universal reprogrammed tracrRNA. These findings extend tracrRNA reprogramming to diverse dsDNA-targeting Cas12 nucleases, expanding the flexibility and versatility of CRISPR-based RNA detection.
    DOI:  https://doi.org/10.1038/s41467-024-50243-x
  22. J Exp Med. 2024 Sep 02. pii: e20240980. [Epub ahead of print]221(9):
    PTPN2 deficiency: Amping up JAK/STAT.
    Joshua M Tobin, Megan A Cooper.
      Identification of monogenic causes of immune dysregulation provides insight into human immune response and signaling pathways associated with autoimmunity. Here, Jeanpierre et al. (https://doi.org/10.1084/jem.20232337) identify new germline variants in the gene encoding PTPN2 associated with loss of regulatory function, enhanced JAK/STAT signaling, and early-onset autoimmunity.
    DOI:  https://doi.org/10.1084/jem.20240980
  23. Nat Commun. 2024 Jul 16. 15(1): 5984
    Divergent evolution of male-determining loci on proto-Y chromosomes of the housefly.
    Xuan Li, Sander Visser, Jae Hak Son, Elzemiek Geuverink, Ece Naz Kıvanç, Yanli Wu, Stephan Schmeing, Martin Pippel, Seyed Yahya Anvar, Martijn A Schenkel, František Marec, Mark D Robinson, Richard P Meisel, Ernst A Wimmer, Louis van de Zande, Daniel Bopp, Leo W Beukeboom.
      Houseflies provide a good experimental model to study the initial evolutionary stages of a primary sex-determining locus because they possess different recently evolved proto-Y chromosomes that contain male-determining loci (M) with the same male-determining gene, Mdmd. We investigate M-loci genomically and cytogenetically revealing distinct molecular architectures among M-loci. M on chromosome V (MV) has two intact Mdmd copies in a palindrome. M on chromosome III (MIII) has tandem duplications containing 88 Mdmd copies (only one intact) and various repeats, including repeats that are XY-prevalent. M on chromosome II (MII) and the Y (MY) share MIII-like architecture, but with fewer repeats. MY additionally shares MV-specific sequence arrangements. Based on these data and karyograms using two probes, one derives from MIII and one Mdmd-specific, we infer evolutionary histories of polymorphic M-loci, which have arisen from unique translocations of Mdmd, embedded in larger DNA fragments, and diverged independently into regions of varying complexity.
    DOI:  https://doi.org/10.1038/s41467-024-50390-1
  24. Cell. 2024 Jul 16. pii: S0092-8674(24)00770-0. [Epub ahead of print]
    From periphery to center stage: 50 years of advancements in innate immunity.
    Susan Carpenter, Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1016/j.cell.2024.07.010
  25. Nat Commun. 2024 Jul 17. 15(1): 6027
    MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data.
    Theodore Sakellaropoulos, Catherine Do, Guimei Jiang, Giulia Cova, Peter Meyn, Dacia Dimartino, Sitharam Ramaswami, Adriana Heguy, Aristotelis Tsirigos, Jane A Skok.
      Aberrations in the capacity of DNA/chromatin modifiers and transcription factors to bind non-coding regions can lead to changes in gene regulation and impact disease phenotypes. However, identifying distal regulatory elements and connecting them with their target genes remains challenging. Here, we present MethNet, a pipeline that integrates large-scale DNA methylation and gene expression data across multiple cancers, to uncover cis regulatory elements (CREs) in a 1 Mb region around every promoter in the genome. MethNet identifies clusters of highly ranked CREs, referred to as 'hubs', which contribute to the regulation of multiple genes and significantly affect patient survival. Promoter-capture Hi-C confirmed that highly ranked associations involve physical interactions between CREs and their gene targets, and CRISPR interference based single-cell RNA Perturb-seq validated the functional impact of CREs. Thus, MethNet-identified CREs represent a valuable resource for unraveling complex mechanisms underlying gene expression, and for prioritizing the verification of predicted non-coding disease hotspots.
    DOI:  https://doi.org/10.1038/s41467-024-50380-3
  26. Nature. 2024 Jul 17.
    Inhibition of IL-11 signalling extends mammalian healthspan and lifespan.
    Anissa A Widjaja, Wei-Wen Lim, Sivakumar Viswanathan, Sonia Chothani, Ben Corden, Cibi Mary Dasan, Joyce Wei Ting Goh, Radiance Lim, Brijesh K Singh, Jessie Tan, Chee Jian Pua, Sze Yun Lim, Eleonora Adami, Sebastian Schafer, Benjamin L George, Mark Sweeney, Chen Xie, Madhulika Tripathi, Natalie A Sims, Norbert Hübner, Enrico Petretto, Dominic J Withers, Lena Ho, Jesus Gil, David Carling, Stuart A Cook.
      For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
    DOI:  https://doi.org/10.1038/s41586-024-07701-9
  27. Nat Genet. 2024 Jul;56(7): 1327
    Measuring nascent transcription in single cells.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-01845-0
  28. Nat Commun. 2024 Jul 16. 15(1): 5964
    Rapid meiotic prophase chromosome movements in Arabidopsis thaliana are linked to essential reorganization at the nuclear envelope.
    Laurence Cromer, Mariana Tiscareno-Andrade, Sandrine Lefranc, Aurélie Chambon, Aurélie Hurel, Manon Brogniez, Julie Guérin, Ivan Le Masson, Gabriele Adam, Delphine Charif, Philippe Andrey, Mathilde Grelon.
      Meiotic rapid prophase chromosome movements (RPMs) require connections between the chromosomes and the cytoskeleton, involving SUN (Sad1/UNC-84)-domain-containing proteins at the inner nuclear envelope (NE). RPMs remain significantly understudied in plants, with respect to their importance in the regulation of meiosis. Here, we demonstrate that Arabidopsis thaliana meiotic centromeres undergo rapid (up to 500 nm/s) and uncoordinated movements during the zygotene and pachytene stages. These centromere movements are not affected by altered chromosome organization and recombination but are abolished in the double mutant sun1 sun2. We also document the changes in chromosome dynamics and nucleus organization during the transition from leptotene to zygotene, including telomere attachment to SUN-enriched NE domains, bouquet formation, and nucleolus displacement, all of which were defective in sun1 sun2. These results establish A. thaliana as a model species for studying the functional implications of meiotic RPMs and demonstrate the mechanistic conservation of telomere-led RPMs in plants.
    DOI:  https://doi.org/10.1038/s41467-024-50169-4
  29. J Exp Med. 2024 Sep 02. pii: e20231725. [Epub ahead of print]221(9):
    SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.
    COVID Human Genetic Effort
      Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
    DOI:  https://doi.org/10.1084/jem.20231725
  30. Nat Commun. 2024 Jul 17. 15(1): 5976
    Inaccurate viral prediction leads to overestimated diversity of the archaeal virome in the human gut.
    Cynthia M Chibani, Shiraz A Shah, Ruth A Schmitz, Stephen Nayfach.
      
    DOI:  https://doi.org/10.1038/s41467-024-49902-w
  31. J Clin Invest. 2024 Jul 15. pii: e183888. [Epub ahead of print]134(14):
    What happens to the brain during pregnancy?
    Andrea M Maxwell.
      
    DOI:  https://doi.org/10.1172/JCI183888
  32. Nat Immunol. 2024 Jul 15.
    Advancements in pathogen immunity and signaling.
    Mads Gyrd-Hansen, Anna Kajaste-Rudnitski, Nicolas Manel, Jan Rehwinkel, Annemarthe G van der Veen, Matteo Iannacone.
      
    DOI:  https://doi.org/10.1038/s41590-024-01905-x
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