bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–10–26
27 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Blood tests are now approved for Alzheimer's: how accurate are they?
  2. IPA brews metabolic balance in gut immunity.
  3. ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery disease.
  4. Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
  5. A lactate-acetate interaction between macrophages and cancer cells drives metastasis.
  6. Scaling back DEI programmes and the loss of scientific talent.
  7. Sweet signals for myelin: glucose sensing redirected to regeneration.
  8. Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.
  9. Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism.
  10. scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
  11. A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging.
  12. A better recipe for generating immune peacemakers.
  13. Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors.
  14. A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.
  15. A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.
  16. Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation.
  17. Integration of hunger and hormonal state gates infant-directed aggression.
  18. Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.
  19. Microglial MEF2C is a uniquely human bridge between neurodevelopment and neurodegeneration.
  20. Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP.
  21. Single-cell RNA profiling of blood CD4+ T cells identifies distinct helper and dysfunctional regulatory clusters in children with SLE.
  22. Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.
  23. Our Common Goal to Prevent Cirrhosis in People With Type 2 Diabetes.
  24. Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.
  25. Homeostasis of glucose and lipid metabolism during physiological responses to a simulated hypoxic high altitude environment.
  26. Adding Rigor to Stress Management for the Treatment of Coronary Artery Disease.
  27. A wearable-based aging clock associates with disease and behavior.
  1. Nature. 2025 Oct 17.
    Blood tests are now approved for Alzheimer's: how accurate are they?
    Katie Kavanagh.
      
    Keywords:  Alzheimer's disease; Brain
    DOI:  https://doi.org/10.1038/d41586-025-03394-w
  2. Nat Metab. 2025 Oct 21.
    IPA brews metabolic balance in gut immunity.
    Jacy Scott, Chaoran Li.
      
    DOI:  https://doi.org/10.1038/s42255-025-01401-y
  3. EMBO Mol Med. 2025 Oct 21.
    ER stress induced mitochondrial dysfunction drives Treg instability in coronary artery disease.
    Smriti Parashar, Mohammad Oliaeimotlagh, Payel Roy, Qingkang Lyu, Anusha Bellapu, Mikhail Fomin, Sunil Kumar, Yan Wang, Chantel C McSkimming, Coleen A McNamara, Klaus Ley.
      Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4+ T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4+ T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.
    Keywords:  Atherosclerosis; ER Stress; Mitochondrial Dysfunction; Tregs; exTregs
    DOI:  https://doi.org/10.1038/s44321-025-00322-3
  4. Sci Immunol. 2025 Oct 24. 10(112): eads9456
    Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
    Jordy Saravia, Nicole M Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil Kc, Seon Ah Lim, Jana L Raynor, Sharad Shrestha, Erienne G Norton, Sarah E La Grange, Camenzind G Robinson, Peter Vogel, Hongbo Chi.
      Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell-specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate-activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell-specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency-associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal "metabolic quiescence reset" state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria-lysosome interplay control Treg cell differentiation and function.
    DOI:  https://doi.org/10.1126/sciimmunol.ads9456
  5. Nat Metab. 2025 Oct 20.
    A lactate-acetate interaction between macrophages and cancer cells drives metastasis.
      
    DOI:  https://doi.org/10.1038/s42255-025-01398-4
  6. Nat Cell Biol. 2025 Oct 23.
    Scaling back DEI programmes and the loss of scientific talent.
    Needhi Bhalla, JoAnn Trejo, Mary Munson.
      
    DOI:  https://doi.org/10.1038/s41556-025-01797-5
  7. Nat Metab. 2025 Oct 22.
    Sweet signals for myelin: glucose sensing redirected to regeneration.
    Andrew R Tee.
      
    DOI:  https://doi.org/10.1038/s42255-025-01392-w
  8. Sci Immunol. 2025 Oct 24. 10(112): eadp0849
    Lipolysis-microlipophagy cascade regulated by adipose triglyceride lipase drives pathogenic adaptive type 2 immunity.
    Hiroyuki Yagyu, Masahiro Kiuchi, Atsushi Sasaki, Eisuke Itakura, Kota Kokubo, Chiaki Iwamura, Atsushi Onodera, Ami Aoki, Takahisa Hishiya, Kaori Tsuji, Takuto Hiramoto, Rie Shinmi, Yuri Sonobe, Takahiro Arano, Kanae Ohishi, Shigenori Baba, Junya Kurita, Tomohisa Iinuma, Syuji Yonekura, Yu Hara, Motoko Y Kimura, Shinichiro Motohashi, Damon J Tumes, Toyoyuki Hanazawa, Takeshi Kaneko, Toshinori Nakayama, Kiyoshi Hirahara.
      A unique subpopulation of memory T helper 2 (TH2) cells expressing the interleukin-33 (IL-33) receptor ST2 drives allergic disease pathogenesis. However, the immunometabolic mechanisms that induce ST2hi memory TH2 cells remain unclear. We show using a mouse model of chronic allergic airway inflammation that long-chain unsaturated fatty acids (LC-UFAs) accumulate in the inflammatory milieu during chronic airway inflammation. Activated TH2 cells take up LC-UFAs, transiently store them in lipid droplets (LDs), and catabolize LDs through lipolysis and microlipophagy. LD catabolism regulated by adipose triglyceride lipase (ATGL) activates peroxisome proliferator-activated receptor γ (PPARγ). PPARγ then binds the Il1rl1 locus encoding ST2 and induces ST2hi effector and memory TH2 cells. In eosinophilic chronic rhinosinusitis, CD45RO+ CD4 T cells in nasal polyps exhibit microlipophagy and an accessible IL1RL1 enhancer, indicating that these mechanisms are conserved in humans. Thus, the storage and catabolism of inflammatory milieu-derived LC-UFAs direct pathogenic adaptive type 2 immunity, offering potential therapeutic strategies for persistent allergic inflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.adp0849
  9. Cell Metab. 2025 Oct 23. pii: S1550-4131(25)00433-4. [Epub ahead of print]
    Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism.
    Jérémy Dufau, Emeline Recazens, Laura Bottin, Camille Bergoglio, Aline Mairal, Karima Chaoui, Marie-Adeline Marques, Veronica Jimenez, Miquel García, Tongtong Wang, Henrik Laurell, Jason S Iacovoni, Remy Flores-Flores, Pierre-Damien Denechaud, Khalil Acheikh Ibn Oumar, Ez-Zoubir Amri, Catherine Postic, Jean-Paul Concordet, Pierre Gourdy, Niklas Mejhert, Mikael Rydén, Odile Burlet-Schiltz, Fatima Bosch, Christian Wolfrum, Etienne Mouisel, Genevieve Tavernier, Dominique Langin.
      In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy. Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue. Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix. Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3). Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting. Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance.
    Keywords:  TGF-β signaling; adipocyte; adipose tissue; cell nucleus; extracellular matrix; hormone-sensitive lipase; lipodystrophy; mitochondrial oxidative phosphorylation; obesity; protein-protein interaction
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.014
  10. Nat Methods. 2025 Oct 22.
    scooby: modeling multimodal genomic profiles from DNA sequence at single-cell resolution.
    Johannes C Hingerl, Laura D Martens, Alexander Karollus, Trevor Manz, Jason D Buenrostro, Fabian J Theis, Julien Gagneur.
      Understanding how regulatory sequences shape gene expression across individual cells is a fundamental challenge in genomics. Joint RNA sequencing and epigenomic profiling provides opportunities to build models capturing sequence determinants across steps of gene expression. However, current models, developed primarily for bulk omics data, fail to capture the cellular heterogeneity and dynamic processes revealed by single-cell multimodal technologies. Here, we introduce scooby, a framework to model genomic profiles of single-cell RNA-sequencing coverage and single-cell assay for transposase-accessible chromatin using sequencing insertions from sequence at single-cell resolution. For this, we leverage the pretrained multiomics profile predictor Borzoi and equip it with a cell-specific decoder. Scooby recapitulates cell-specific expression levels of held-out genes and identifies regulators and their putative target genes. Moreover, scooby allows resolving single-cell effects of bulk expression quantitative trait loci and delineating their impact on chromatin accessibility and gene expression. We anticipate scooby to aid unraveling the complexities of gene regulation at the resolution of individual cells.
    DOI:  https://doi.org/10.1038/s41592-025-02854-5
  11. Nat Neurosci. 2025 Oct 23.
    A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging.
    Patrick W Sheehan, Stuart B Fass, Darshan Sapkota, Sylvia Kang, Henry C Hollis, Jennifer H Lawrence, Sohui Park, Ashish Sharma, Dorothy P Schafer, Ron C Anafi, Joseph D Dougherty, John D Fryer, Erik S Musiek.
      While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging.
    DOI:  https://doi.org/10.1038/s41593-025-02067-1
  12. Science. 2025 Oct 23. 390(6771): 326
    A better recipe for generating immune peacemakers.
    Catherine Offord.
      Nobel laureate develops new method of making regulatory T cells that could treat autoimmune conditions.
    DOI:  https://doi.org/10.1126/science.aed2827
  13. Proc Natl Acad Sci U S A. 2025 Oct 28. 122(43): e2509412122
    Linker histone regulates the myeloid versus lymphoid bifurcation of multipotent hematopoietic stem and progenitors.
    Kutay Karatepe, Bruna Mafra de Faria, Jian Zhang, Xinyue Chen, Hugo Pinto, Dmitry Fyodorov, Esen Sefik, Michael A Willcockson, Richard A Flavell, Arthur I Skoultchi, Shangqin Guo.
      Myeloid-biased differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) occurs with aging or exhaustion. The molecular mechanism(s) responsible for this fate bias remain unclear. Here, we report that linker histone regulates HSPC fate choice at the lymphoid versus myeloid bifurcation. Linker histones package nucleosomes and compact chromatin. HSPCs expressing a doxycycline (dox)-inducible H1.0 transgene favor the lymphoid fate, display strengthened nucleosome organization, and reduced chromatin accessibility at subsets of genomic regions. The genomic regions showing reduced chromatin accessibility host many known marker genes of myeloid-biased HSCs. The transcription factor Hlf is located in one of the most differentially closed regions, whose chromatin accessibility and gene expression are reduced in H1.0high HSPCs. Failure to reduce Hlf expression in multipotential HSPCs abrogates the H1.0-endowed lymphoid potential. Furthermore, HSPCs display aspartyl protease-dependent H1.0 decreases, especially in response to interferon alpha (IFNα). Aspartyl protease inhibitors preserve endogenous H1.0 levels and promote the lymphoid fate of wild type HSPCs. Thus, our work elucidates a molecular scenario of how myeloid bias arises and uncovers a point of intervention for correcting myeloid skewed hematopoiesis.
    Keywords:  inflammation; linker histone; myeloid bias
    DOI:  https://doi.org/10.1073/pnas.2509412122
  14. Mol Cell. 2025 Oct 23. pii: S1097-2765(25)00817-2. [Epub ahead of print]
    A structural basis for chaperone repression of stress signaling from the endoplasmic reticulum.
    Lisa Neidhardt, Joanne Tung, Miriam Kuchersky, Jakub Milczarek, Vasileios Kargas, Katherine Stott, Rina Rosenzweig, David Ron, Yahui Yan.
      The endoplasmic reticulum (ER) unfolded protein response (UPR) is tuned by the balance between unfolded proteins and chaperones. Reserve chaperones suppress UPR transducers via their stress-sensing luminal domains, but the underlying mechanisms remain unclear. The ER chaperone AGR2 is known to repress the UPR transducer IRE1β. Here, structural prediction, X-ray crystallography, and NMR spectroscopy identify critical interactions between an AGR2 monomer and a regulatory loop in IRE1β's luminal domain. However, in the repressive complex, it is an AGR2 dimer that binds IRE1β. Cryoelectron microscopy (cryo-EM) reconstruction explains this feature: one AGR2 protomer engages the regulatory loop, while the second asymmetrically binds IRE1β's luminal domain's C terminus, blocking IRE1β-activating dimerization. Molecular dynamic simulations indicate that the second, disruptive AGR2 protomer exploits rare fluctuations in the IRE1β dimer that expose its binding site. Thus, AGR2 disrupts IRE1β dimers to suppress the UPR, priming the system for activation by chaperone clients that compete for AGR2.
    Keywords:  endoplasmic reticulum; intestinal mucin; molecular chaperones; protein multimerization; signal transduction; transmembrane protein; unconventional splicing; unfolded protein response
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.032
  15. Nat Immunol. 2025 Oct 22.
    A unified multimodal single-cell framework reveals a discrete state model of hematopoiesis in mice.
    Kyle Ferchen, Xuan Zhang, Kairavee Thakkar, Guangyuan Li, David Bernardicius, Sidharth Sen, Priyanka Rawat, Andre Olsson, Sierra N Bennett, Crystal Potter, Fred D Finkelman, Josh Croteau, Samantha Morris, Harinder Singh, Nathan Salomonis, H Leighton Grimes.
      Large-scale, unbiased single-cell genomics studies of complex developmental compartments, such as hematopoiesis, have inferred novel cell states and trajectories; however, further characterization has been hampered by difficulty isolating cells corresponding to discrete genomic states. To address this, we present a framework that integrates multimodal single-cell analyses (RNA, surface protein and chromatin) with high-dimensional flow cytometry and enables semiautomated enrichment and functional characterization of diverse cell states. Our approach combines transcription factor expression with chromatin activity to uncover hierarchical gene regulatory networks driving these states. We delineated and isolated rare bone marrow Lin-Sca-CD117+CD27+ multilineage cell states ('MultiLin'), validated predicted lineage trajectories and mapped differentiation potentials. Additionally, we used transcription factor activity on chromatin to trace and isolate multilineage progenitors undergoing multipotent to oligopotent lineage restriction. In the proposed model of steady-state hematopoiesis, discrete states governed developmental trajectories. This framework provides a scalable solution for isolating and characterizing novel cell states across different biological systems.
    DOI:  https://doi.org/10.1038/s41590-025-02307-3
  16. Nat Commun. 2025 Oct 20. 16(1): 8966
    Optineurin is an adaptor protein for ubiquitinated substrates in Golgi membrane-associated degradation.
    Yoichi Nibe-Shirakihara, Shinya Honda, Satoko Arakawa, Satoru Torii, Hajime Tajima Sakurai, Hirofumi Yamaguchi, Shigeru Oshima, Ryuichi Okamoto, Michael Lazarou, Hideshi Kawakami, Shigeomi Shimizu.
      Golgi membrane-associated degradation (GOMED) is a process that leading to the degradation of proteins that have passed through the trans-Golgi membranes upon Golgi stress. GOMED is morphologically similar to autophagy, but the substrates degraded are different, and they thus have different biological roles. Although the substrate recognition mechanism of autophagy has been clarified in detail, that of GOMED is completely unknown. Here we report that GOMED degrades its substrate proteins selectively via optineurin (OPTN), as we found that the degradation of GOMED substrates is s`uppressed by the loss of OPTN. OPTN binds to K33 polyubiquitin-tagged proteins that have passed through the Golgi, which are then incorporated into GOMED structures for eventual degradation. In vivo, GOMED is known to be involved in the removal of mitochondria from erythrocytes, and in Optn-deficient mice, mitochondria are not degraded by GOMED, resulting in the appearance of erythrocytes containing mitochondria. These findings provide insight into the substrate recognition mechanism of GOMED.
    DOI:  https://doi.org/10.1038/s41467-025-64400-3
  17. Nature. 2025 Oct 22.
    Integration of hunger and hormonal state gates infant-directed aggression.
    Mingran Cao, Rachida Ammari, Maxwell X Chen, Patty Wai, Bradley B Jamieson, Swang Liang, Basma F A Husain, Aashna Sahni, Nathalie Legrave, Irene Salgarella, James MacRae, Molly Strom, Johannes Kohl.
      Social behaviour is substantially shaped by internal physiological states. Although progress has been made in understanding how individual states such as hunger, stress or arousal modulate behaviour1-9, animals experience multiple states at any given time10. The neural mechanisms that integrate such orthogonal states-and how this integration affects behaviour-remain poorly understood. Here we report how hunger and oestrous state converge on neurons in the medial preoptic area (MPOA) to shape infant-directed behaviour. We find that hunger promotes pup-directed aggression in normally non-aggressive virgin female mice. This behavioural switch occurs through the inhibition of MPOA neurons, driven by the release of neuropeptide Y from Agouti-related peptide-expressing neurons in the arcuate nucleus (ArcAgRP neurons). The propensity for hunger-induced aggression is set by reproductive state, with MPOA neurons detecting changes in the progesterone to oestradiol ratio across the oestrous cycle. Hunger and oestrous state converge on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which sets the baseline activity and excitability of MPOA neurons. Using microendoscopy imaging, we confirm these findings in vivo, revealing that MPOA neurons encode a state for pup-directed aggression. This work provides a mechanistic understanding of how multiple physiological states are integrated to flexibly control social behaviour.
    DOI:  https://doi.org/10.1038/s41586-025-09651-2
  18. Nat Commun. 2025 Oct 20. 16(1): 9257
    Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.
    Karen Yap, Tek Hong Chung, Erin C Hedges, Agnes L Nishimura, Christopher E Shaw, Eugene V Makeyev.
      RNAs engage diverse protein partners and localize to specific subcellular compartments, yet dissecting proteomes associated with low-abundance or dispersed RNA molecules remains a challenge. We present an enhanced hybridization-proximity labeling (HyPro) technology for in situ proteome profiling of endogenously expressed RNA microcompartments. We re-engineer the HyPro enzyme and optimize proximity biotinylation conditions to identify proteins associated with compact RNA-containing nuclear bodies, small pre-mRNA clusters, and individual transcripts. Applying this approach to pathogenic G4C2 repeat-containing C9orf72 RNAs, retained as single-molecule foci in the nuclei of amyotrophic lateral sclerosis (ALS) patient-derived pluripotent stem cells, we reveal extensive interactions with disease-linked paraspeckle markers and a specific set of pre-mRNA splicing factors. These findings highlight early RNA processing and localization defects in ALS that may contribute to this late-onset neurodegenerative disorder. Overall, HyPro provides a broadly applicable platform for mapping RNA-protein interactions, enabling insights into RNA biology and its dysregulation in disease.
    DOI:  https://doi.org/10.1038/s41467-025-64282-5
  19. Nat Immunol. 2025 Oct 22.
    Microglial MEF2C is a uniquely human bridge between neurodevelopment and neurodegeneration.
    Ryan J Rahman, Mariko L Bennett.
      
    DOI:  https://doi.org/10.1038/s41590-025-02313-5
  20. Nat Commun. 2025 Oct 22. 16(1): 9331
    Deciphering histone mark-specific fine-scale chromatin organization at high resolution with Micro-C-ChIP.
    Mariia Metelova, Maria Louisa Vigh, Nils Krietenstein.
      The regulation of cell-type-specific transcription relies on complex 3D interactions between promoters and distal regulatory elements. Although Hi-C has advanced our understanding of genome architecture, its high sequencing demand limits use in large-scale or time course experiments. We introduce Micro-C-ChIP, a strategy combining Micro-C with chromatin immunoprecipitation to map 3D genome organization at nucleosome resolution for defined histone modifications. We profile H3K4me3 and H3K27me3-specific 3D genome architecture in mouse embryonic stem cells (mESC), hTERT-immortalized human retinal pigment epithelial (hTERT-RPE1) cells, and HCT-116 RAD21-mAID-mClover (HCT-116 RAD21-mAC) cells. We validate that Micro-C-ChIP reveals genuine 3D genome features that are not driven by ChIP-enrichment bias. We identify extensive promoter-promoter contact networks in mESCs and hTERT-RPE1, and resolve the distinct 3D architecture of bivalent promoters in mESCs. Together, our results demonstrate that Micro-C-ChIP is a high-resolution, cost-efficient approach to study histone-modification-specific chromatin folding.
    DOI:  https://doi.org/10.1038/s41467-025-64350-w
  21. Nat Immunol. 2025 Oct 21.
    Single-cell RNA profiling of blood CD4+ T cells identifies distinct helper and dysfunctional regulatory clusters in children with SLE.
    Preetha Balasubramanian, Uthra Balaji, Marina Silva Santos, Jeanine Baisch, Cynthia Smitherman, Lynnette Walters, Paola Sparagana, Lorien Nassi, Katie Stewart, Julie Fuller, Terry Means, Virginia Savova, Jacques F Banchereau, Tracey Wright, Virginia Pascual, Jinghua Gu, Simone Caielli.
      To characterize the complexity of the CD4⁺ T cell compartment in patients with systemic lupus erythematosus (SLE), we performed single-cell RNA sequencing of sorted blood CD4⁺ T cells from pediatric patients and healthy donors. We identified naive, memory, regulatory T (Treg) cell, proliferative and interferon-stimulated gene-high (ISG-high) clusters. Within the memory compartment, both follicular and peripheral helper cells were expanded in patients with lupus nephritis and/or high disease activity. Cytotoxic signatures were enriched in effector memory T cells re-expressing CD45RA (TEMRA), as well as in two memory subclusters, one of which overlapped with T helper 10-like cells (TH10). Notably, we observed an expansion of dysfunctional Treg cells in patients with lupus nephritis, along with upregulation of TLR5 and FCRL3 in SLE-naive Treg cells, suggesting a potential link with mucosal microbial dysbiosis. These findings highlight distinct CD4⁺ T cell subsets that may contribute to aberrant antibody responses and impaired immune regulation in SLE.
    DOI:  https://doi.org/10.1038/s41590-025-02297-2
  22. Nat Commun. 2025 Oct 23. 16(1): 9370
    Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.
    Vikas Yadav, Sarthak Sahoo, Nitish Malhotra, Richa Mishra, Sreesa Sreedharan, Raju S Rajmani, Siva Shanmugam, Radha K Shandil, Shridhar Narayanan, Vivek V Thacker, Sunil Laxman, Mohit Kumar Jolly, Aswin Sai Narain Seshasayee, Amit Singh.
      Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance.
    DOI:  https://doi.org/10.1038/s41467-025-64407-w
  23. Diabetes Care. 2025 Nov 01. 48(11): e155
    Our Common Goal to Prevent Cirrhosis in People With Type 2 Diabetes.
    Kenneth Cusi.
      
    DOI:  https://doi.org/10.2337/dci25-0079
  24. Nat Metab. 2025 Oct 20.
    Tumour-associated macrophages serve as an acetate reservoir to drive hepatocellular carcinoma metastasis.
    Li Shen, Shenghao Wang, Chao Gao, Qin Li, Shuya Feng, Weiyan Sun, Xu Liu, Yiyi Ba, Yihui Chu, Yu Zhou, Junjie Pan, Hao Xu, Xu Zhang, Wenwei Zhu, Lunxiu Qin, Ming Lu.
      Increased acetyl-coenzyme A (acetyl-CoA) generation facilitates cancer metastasis and represents a critical metabolic characteristic of metastatic cancers. To maintain high acetyl-CoA levels, cancer cells often enhance the uptake of acetate for acetyl-CoA biosynthesis. However, the microenvironmental source of acetate remains largely unknown. Here we demonstrate that acetate is secreted by tumour-associated macrophages (TAMs) and taken up by hepatocellular carcinoma (HCC) cells to support acetate accumulation. Mechanistically, HCC cell-derived lactate activates the lipid peroxidation-aldehyde dehydrogenase 2 (ALDH2) pathway in TAMs, which promotes the TAMs' acetate production and secretion. Inhibition of ALDH2 or of lipid peroxidation in TAMs abrogates acetate-induced migration of HCC cells in vitro. In an orthotopic HCC model involving male mice, genetic ablation of ALDH2 in TAMs reduces HCC cell acetate levels and HCC lung metastases. Collectively, our findings reveal a metabolic interaction between HCC cells and TAMs-involving lactate, lipid peroxidation and acetate-and position TAMs as an acetate reservoir that drives HCC metastasis.
    DOI:  https://doi.org/10.1038/s42255-025-01393-9
  25. Nat Commun. 2025 Oct 24. 16(1): 9406
    Homeostasis of glucose and lipid metabolism during physiological responses to a simulated hypoxic high altitude environment.
    Yi Lin, Bingyu Li, Xinying Shi, Yangkang Chen, Shengkai Pan, Zhenzhen Lin, Zhongru Gu, Frank Hailer, Li Hu, Xiangjiang Zhan.
      Homeostasis facilitates maintenance of physiological processes despite extrinsic fluctuations. In aerobic organisms, homeostasis is mainly fueled by metabolism of glucose and lipids, and requires oxygen as a metabolic substrate. Lack of oxygen can therefore trigger an imbalance of homeostasis in vivo. How animals living at high altitude hypoxic conditions can maintain homeostasis between the two types of metabolism remains largely unknown. Here, we establish a 'falconized' mouse model based on an adaptive EPAS1 genetic variant identified from saker falcons (Falco cherrug) on the Qinghai-Tibet Plateau (QTP). We show that homeostasis between glucose and lipid metabolism in the liver under chronic hypoxia is maintained in male falconized mice. This homeostasis is mediated by genetic factors and behavioral plasticity, resulting in higher survival rates even under acute hypoxia than wild type mice. Our study highlights a key role of metabolic homeostasis maintenance for survival in extreme environments, and provides potential targets for the treatment of associated metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-025-64110-w
  26. JAMA Netw Open. 2025 Oct 01. 8(10): e2538424
    Adding Rigor to Stress Management for the Treatment of Coronary Artery Disease.
    Lawson R Wulsin.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.38424
  27. Nat Commun. 2025 Oct 20. 16(1): 9264
    A wearable-based aging clock associates with disease and behavior.
    Andrew C Miller, Joseph Futoma, Salar Abbaspourazad, Christina Heinze-Deml, Saba Emrani, Ian Shapiro, Guillermo Sapiro.
      Aging biomarkers play a vital role in understanding longevity, with the potential to improve clinical decisions and interventions. Existing aging clocks typically use blood, vitals, or imaging collected in a clinical setting. Wearables, in contrast, can make frequent and inexpensive measurements throughout daily living. Here we develop PpgAge, an aging clock using photoplethysmography at the wrist from a consumer wearable. Using the Apple Heart & Movement Study (n = 213,593 participants; >149 million participant-days), our observational analysis shows that this non-invasive and passively collected aging clock accurately predicts chronological age and captures signs of healthy aging. Participants with an elevated PpgAge gap (i.e., predicted age greater than chronological age) have significantly higher diagnosis rates of heart disease, heart failure, and diabetes. Elevated PpgAge gap is also a significant predictor of incident heart disease events (and new diagnoses) when controlling for relevant risk factors. PpgAge also associates with behavior, including smoking, exercise, and sleep. Longitudinally, PpgAge exhibits a sharp increase during pregnancy and concurrent with certain types of cardiac events.
    DOI:  https://doi.org/10.1038/s41467-025-64275-4
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