Stem Cell ReportsPub Date : 2026-10-15DOI: 10.1016/j.stemcr.2026.103116
Roy W Hwang, Ying Betty Li, Richard Marcotte, Will Costain, Anna Jezierski
{"title":"Programming brain endothelial identity: Transcription factor and genome engineering approaches to improve iPSC-derived BBB models.","authors":"Roy W Hwang, Ying Betty Li, Richard Marcotte, Will Costain, Anna Jezierski","doi":"10.1016/j.stemcr.2026.103116","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103116","url":null,"abstract":"<p><p>Human induced pluripotent stem cell-derived brain endothelial-like cells (iBECs) serve as important human relevant in vitro blood-brain barrier (BBB) models for evaluating central nervous system (CNS)-targeted therapies. However, conventional differentiation protocols often generate heterogeneous populations constrained by incomplete endothelial maturation. Overcoming these limitations requires precise control over developmental gene regulatory networks throughout differentiation. This review examines transcription factor-based forward reprogramming strategies designed to induce brain endothelial cell fate and prime BBB identity. Integrating these approaches with novel genome engineering tools enables the rational design of next generation BBB models with improved physiological fidelity and predictive power for CNS therapeutic discovery and validation.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103116"},"PeriodicalIF":5.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-15DOI: 10.1016/j.stemcr.2026.103120
Christina Thapa, Emily K Oh, David Sirkin, Jennifer Lahey, Sol Díaz de León Guerrerro, Ada McCarroll, Prarthana Gowda, Hanwen Zhang, Alexandra Barishman, Lilia Peyton, Siwei Zhang, Rebecca M Pollak, Ronald P Hart, Carlos N Pato, Anat Kreimer, Jennifer G Mulle, Alan R Sanders, Zhiping P Pang, Jubao Duan
{"title":"Female iPSC X chromosome inactivation erosion and its transcriptomic effects during CRISPR gene editing and neural differentiation.","authors":"Christina Thapa, Emily K Oh, David Sirkin, Jennifer Lahey, Sol Díaz de León Guerrerro, Ada McCarroll, Prarthana Gowda, Hanwen Zhang, Alexandra Barishman, Lilia Peyton, Siwei Zhang, Rebecca M Pollak, Ronald P Hart, Carlos N Pato, Anat Kreimer, Jennifer G Mulle, Alan R Sanders, Zhiping P Pang, Jubao Duan","doi":"10.1016/j.stemcr.2026.103120","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103120","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs), together with CRISPR editing, are commonly used for studying neurodevelopmental disorders. Female iPSCs gradually lose the expression of the noncoding X chromosome inactive-specific transcript (XIST), leading to random X chromosome inactivation (XCI) erosion that affects both X-linked and autosomal gene expression. However, the effects of CRISPR editing and neural differentiation on XCI erosion and how this may confound a real-world analysis of differentially expressed genes (DEGs) are poorly understood. Here, we analyzed hundreds of RNA sequencing (RNA-seq) samples of CRISPR-edited iPSC lines for 66 genes and the matched single-neuron RNA-seq data. We found variable XCI in CRISPR-edited female iPSCs, which was largely preserved in iPSC-derived neurons and predominantly influenced X-linked genes. Mechanistically, XIST mediates allele-specific epigenetic regulation of both X-linked and autosomal genes, with the former showing stronger allele-specific expression (ASE) bias that affects neurodevelopmental genes. These results have significant implications in hiPSC-based modeling of neurodevelopmental disorders.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103120"},"PeriodicalIF":5.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-15DOI: 10.1016/j.stemcr.2026.103117
Ping Wang, Xianhao Li, Wendong Liu, Jiewei Wang, Li Hua Jin
{"title":"Microbiota-derived SCFAs modulate Socs36E-mediated feedback to regulate intestinal stem cell proliferation upon Atg4 loss in Drosophila.","authors":"Ping Wang, Xianhao Li, Wendong Liu, Jiewei Wang, Li Hua Jin","doi":"10.1016/j.stemcr.2026.103117","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103117","url":null,"abstract":"<p><p>Microbial metabolites affect host physiology, but how they link genetic defects to abnormal stem cell behavior is unclear. In Drosophila, losing Atg4 in progenitors changes the gut microbiota and raises short-chain fatty acids (SCFAs), such as acetate and propionate. These SCFAs increase intracellular acetyl-CoA, which boosts acetylation by inhibiting histone deacetylases (HDACs) and activating multiple histone acetyltransferases. Chromatin immunoprecipitation identifies Socs36E as a direct acetylation target. Socs36E upregulation serves as a feedback brake on EGFR signaling. However, this brake is too weak to stop sustained proliferation, causing intestinal stem cell overgrowth. These phenotypes are abolished in a germ-free niche and can be recapitulated by SCFA-producing bacteria. Our results support a model where niche-derived metabolites drive locus-specific acetylation of Socs36E, modulating a key homeostatic node and influencing stem cell fate decisions.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103117"},"PeriodicalIF":5.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-15DOI: 10.1016/j.stemcr.2026.103119
Muhammad Irfanur Rashid, James Kiley, Karim Azzag, Sarah B Crist, Ethan Murphy, Joshua Lihnakevic, Laura Hocum Stone, Jody L Janecek, Parthasarathy Rangarajan, Aline M S Yamashita, Neha Dhoke, Arreh Jain, Sabarinathan Ramachandran, Melanie L Graham, Rita C R Perlingeiro
{"title":"Donor-intrinsic regenerative potential outweighs histocompatibility in iPSC-derived skeletal muscle engraftment in nonhuman primates.","authors":"Muhammad Irfanur Rashid, James Kiley, Karim Azzag, Sarah B Crist, Ethan Murphy, Joshua Lihnakevic, Laura Hocum Stone, Jody L Janecek, Parthasarathy Rangarajan, Aline M S Yamashita, Neha Dhoke, Arreh Jain, Sabarinathan Ramachandran, Melanie L Graham, Rita C R Perlingeiro","doi":"10.1016/j.stemcr.2026.103119","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103119","url":null,"abstract":"<p><p>Cell-based regenerative therapies represent a promising platform for muscular dystrophies, but the role of histocompatibility for muscle engraftment remains poorly defined. Given their close genetic relationship to humans, nonhuman primate (NHP) models provide an ideal system to investigate this question. Here, we generated myogenic progenitors from induced pluripotent stem cell (iPSC) lines derived from five major histocompatibility complex (MHC)-typed Mauritian-origin cynomolgus macaques (MCMs). Following extensive characterization, one iPSC clone from each donor was selected for transplantation across distinct MHC matching conditions, including fully matched, partially matched, and mismatched recipient-donor pairs. We found that variation in regenerative potential was primarily donor-intrinsic. Strikingly, fully mismatched donor-derived myogenic progenitors exhibiting high regenerative potential consistently outperformed partially and fully matched grafts across recipients. Our results suggest that, under clinically relevant immunosuppression, donor-intrinsic regenerative potential may outweigh histocompatibility as a determinant of early skeletal muscle engraftment, supporting the development of broadly applicable off-the-shelf allogeneic iPSC-based therapies for muscular dystrophies.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103119"},"PeriodicalIF":5.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-15DOI: 10.1016/j.stemcr.2026.103118
M G E Rommel, T Cool, A Rodriguez Y Baena, S Saini, P Medina, C Mattingly, E Bachinsky, S Chattopadhyaya, B A Manso, S Rajendiran, A K Worthington, D M Poscablo, A Deguzman, P Q Wimer, I M Voelker, T Berger-Cahn, L Langroudi, A F Svendsen, A Shariati, S Carpenter, D F Boyd, E C Forsberg
{"title":"Perinatal nicotine exposure disrupts hematopoietic stem cell development and elevates influenza severity in adulthood.","authors":"M G E Rommel, T Cool, A Rodriguez Y Baena, S Saini, P Medina, C Mattingly, E Bachinsky, S Chattopadhyaya, B A Manso, S Rajendiran, A K Worthington, D M Poscablo, A Deguzman, P Q Wimer, I M Voelker, T Berger-Cahn, L Langroudi, A F Svendsen, A Shariati, S Carpenter, D F Boyd, E C Forsberg","doi":"10.1016/j.stemcr.2026.103118","DOIUrl":"https://doi.org/10.1016/j.stemcr.2026.103118","url":null,"abstract":"<p><p>Developmental exposures profoundly shape lifelong health by altering disease resilience later in life. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we establish perinatal nicotine exposure (PNE) as a mouse model of developmental maladaptive immunity, wherein early-life environmental insults permanently alter HSCs. We show that PNE selectively disrupts the establishment of HSCs and tissue-resident, but not circulating, immune cells. Remarkably, the specific decrease of HSCs and lung-resident immune cells persists into adulthood. Single-cell transcriptomics revealed durable molecular reprogramming of adult PNE HSCs, with inverse regulation of positive trained immunity signatures. Functionally, adult PNE offspring challenged with respiratory virus exhibit exacerbated immune maladaptation, marked by increased weight loss, deteriorated lung pathology, hyper-permeability of pulmonary vasculature, tissue-resident macrophage depletion, and exaggerated neutrophil recruitment. Together, our findings establish that PNE imprints durable maladaptive immunity involving changes in HSCs and their progeny, suggesting a hematopoietic origin for the PNE-induced respiratory vulnerability.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103118"},"PeriodicalIF":5.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149196604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-13Epub Date: 2026-09-24DOI: 10.1016/j.stemcr.2026.103088
Xin Shao, Fan Wu, Yang Song, Peng Gao, Kun Qi, Liying Wang
{"title":"Diminished RELB impairs osteogenesis in mature periodontal ligament stem cells.","authors":"Xin Shao, Fan Wu, Yang Song, Peng Gao, Kun Qi, Liying Wang","doi":"10.1016/j.stemcr.2026.103088","DOIUrl":"10.1016/j.stemcr.2026.103088","url":null,"abstract":"<p><p>Although periodontal ligament stem cells (PDLSCs) are pivotal for periodontal tissue regeneration, their regenerative capacity diminishes with the PDL maturity. To elucidate the mechanisms underlying this phenomenon, we performed single-cell RNA sequencing (scRNA-seq) on immature and mature human PDL tissues to characterize the heterogeneity and predict critical regulators affecting osteogenic capacity of PDLSCs. Subsequently, the predicted role of RELB was experimentally validated both in vitro and in vivo using small interfering RNA. The scRNA-seq analysis revealed significant heterogeneity within the PDLSC population. Notably, PDLSC-5 subtype, which exhibited osteogenic potential and positioned at the terminus of the pseudotime trajectory, was markedly reduced in mature PDL tissues. RELB was specifically overexpressed in PDLSC-5 and identified as a key transcription factor (TF) for this subcluster. Knockdown of RELB significantly inhibited the osteogenic differentiation capacity of PDLSCs in vitro and bone formation potential in vivo at both developmental stages. This inhibitory effect appears to be mediated, at least in part, through the downregulation of its target gene, superoxide dismutase 2 (SOD2). Our findings demonstrate that the proportion of PDLSCs with osteogenic ability significantly declines with maturity, accounting for the diminished regeneration capacity of mature periodontal tissue. Furthermore, RELB was identified as a crucial TF for maintaining the osteogenic potential of PDLSCs. These results provide a theoretical basis for strategies aimed at optimizing the bone regeneration capacity of PDLSCs.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103088"},"PeriodicalIF":5.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-13Epub Date: 2026-09-17DOI: 10.1016/j.stemcr.2026.103081
Giulia Spennati, Nicole Vo, Mary C Regier, Heather H Ward, Vivek Das, Anil Karihaloo, Benjamin S Freedman
{"title":"Elevated glucose in kidney organoids induces tissue-intrinsic inflammation driving epithelial detachment.","authors":"Giulia Spennati, Nicole Vo, Mary C Regier, Heather H Ward, Vivek Das, Anil Karihaloo, Benjamin S Freedman","doi":"10.1016/j.stemcr.2026.103081","DOIUrl":"10.1016/j.stemcr.2026.103081","url":null,"abstract":"<p><p>Diabetic kidney disease involves hyperglycemia, inflammation, and epithelial cell dysfunction, but the relationship between these factors is not well understood. We demonstrate that human kidney organoids treated with elevated glucose exhibit a phenotype of epithelial detachment driven by tissue-intrinsic upregulation of proinflammatory cytokines, which can be targeted therapeutically. High glucose induces morphological deterioration of organoids featuring podocyte and tubular cell detachment without cytotoxicity. Cytokine addition sensitizes organoids to intermediate concentrations of elevated glucose. Transcriptomic analysis reveals that high glucose levels affect cytokine, inflammation, signaling, and cell adhesion pathways, resembling changes in human diabetic kidneys. Inhibitors of cytokines and signaling pathways rescue the high glucose phenotype, which is independent of osmotic effects. Thus, elevated glucose triggers a tissue-intrinsic inflammatory cascade to produce an organ-specific phenotype in epithelial cells. This paradigm is relevant for understanding and potentially treating diabetic complications in the kidneys and possibly other organs.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103081"},"PeriodicalIF":5.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148991443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-13Epub Date: 2026-09-24DOI: 10.1016/j.stemcr.2026.103087
Xiao-Xue Dong, Wendy W Y Choi, Mai Ahmed, Haruka Nishimura, Ai Tian, David Millar, Afrin Bhattacharya, Aditi Aggarwal, Liona Vu, Octavia Yifang Weng, Roseanne Nguyen, Pragnya Chakraborty, Lu-Yang Wang, Michael D Wilson, Qiang Shu, Xuekun Li, Yun-Cheng Wu, Julien Muffat, Yun Li
{"title":"HOPX regulates the development and lineage progression of human stem cell-derived outer radial glia-like cells.","authors":"Xiao-Xue Dong, Wendy W Y Choi, Mai Ahmed, Haruka Nishimura, Ai Tian, David Millar, Afrin Bhattacharya, Aditi Aggarwal, Liona Vu, Octavia Yifang Weng, Roseanne Nguyen, Pragnya Chakraborty, Lu-Yang Wang, Michael D Wilson, Qiang Shu, Xuekun Li, Yun-Cheng Wu, Julien Muffat, Yun Li","doi":"10.1016/j.stemcr.2026.103087","DOIUrl":"10.1016/j.stemcr.2026.103087","url":null,"abstract":"<p><p>Outer radial glia (oRG) are abundant in the human fetal cortex but rare in rodents, yet their molecular regulation remains poorly understood. Although the homeodomain-only protein X (HOPX) is a well-established oRG marker, its functional role in human cortical development remains undefined. Using CRISPR-Cas9 gene editing in human pluripotent stem cells, we show that HOPX loss impairs the expansion and lineage progression of oRG-like cells in two-dimensional neural cultures and three-dimensional cortical organoids. HOPX knockout precursors exhibit reduced proliferation, diminished neurogenesis, and premature differentiation toward astrocytic and oligodendrocytic lineages. HOPX-deficient organoids display reduced outer subventricular zone size, decreased neuronal output, and early gliogenesis. Mechanistically, HOPX loss impairs PI3K-mTOR signaling. Transcriptomic analysis identifies HOPX-regulated programs governing gliogenic competence, mTOR, and Wnt signaling. Together, these findings identify HOPX as an important regulator of oRG-like cell maintenance and the neurogenic-gliogenic balance, providing insight into the molecular programs governing human neural progenitor expansion.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103087"},"PeriodicalIF":5.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ROCK inhibition suppresses host blastomere-mediated elimination and enhances trophoblast stem cell contribution in mouse chimeras.","authors":"Baoxing Dong, Kuisheng Liu, Chenxiang Xi, Sheng Wang, Yifan Sheng, Jiani Xiang, Jiayu Chen, Yingdong Liu, Dandan Bai, Shanyao Liu, Xia Tu, Xiaochen Kou, Yanhong Zhao, Jiqing Yin, Hong Wang, Binya Liu, Changle Ma, Shaorong Gao, Wenqiang Liu","doi":"10.1016/j.stemcr.2026.103111","DOIUrl":"10.1016/j.stemcr.2026.103111","url":null,"abstract":"<p><p>Trophoblast stem cells (TSCs) play a crucial role in modeling the complex dynamics of maternal-fetal morphogenesis and placental development. However, their utility is hindered by low contribution rates in embryonic chimeras. Here, we reveal that during the 8-cell mouse embryo aggregation, host blastomeres selectively eliminate donor TSCs through an actin-dependent, phagocytic-like process and degrade them via lysosomal pathways, acting as a developmental quality-control mechanism. Notably, modulating cytoskeletal dynamics via Rho/ROCK pathway inhibition markedly suppresses this host-mediated clearance, enhancing donor TSC retention and contribution to extraembryonic tissues in pre- and post-implantation chimeras without compromising embryonic viability. Overall, our findings identify host blastomere-mediated elimination as an early barrier to TSC chimerism and establish transient ROCK inhibition as a strategy for improving TSC contribution during placental development.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103111"},"PeriodicalIF":5.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stem Cell ReportsPub Date : 2026-10-13Epub Date: 2026-09-03DOI: 10.1016/j.stemcr.2026.103075
Nick G P Bovee, Ehsan Habibi, Zicong Liu, Stefan H A Hoogland, Siebren Frölich, Daniëlle Diepenbroek, Kim C M Bosman, Julia Arand, Irina A Maksakova, Anouk Klein Kranenbarg, Jörn Walter, Arie B Brinkman, Klaas W Mulder, Joop H Jansen, Michiel Vermeulen, Matthew Lorincz, Hendrik G Stunnenberg, Hendrik Marks
{"title":"Methylome profiling of SetDB1-deficient ESCs reveals coordinated epigenetic cross-talk during pluripotency.","authors":"Nick G P Bovee, Ehsan Habibi, Zicong Liu, Stefan H A Hoogland, Siebren Frölich, Daniëlle Diepenbroek, Kim C M Bosman, Julia Arand, Irina A Maksakova, Anouk Klein Kranenbarg, Jörn Walter, Arie B Brinkman, Klaas W Mulder, Joop H Jansen, Michiel Vermeulen, Matthew Lorincz, Hendrik G Stunnenberg, Hendrik Marks","doi":"10.1016/j.stemcr.2026.103075","DOIUrl":"10.1016/j.stemcr.2026.103075","url":null,"abstract":"<p><p>SetDB1 is best known for catalyzing H3K9me3, but it also influences H3K27me3 deposition, CTCF-binding, and DNA methylation (DNAme). Given the interplay between DNAme and the other epigenetic features, we profiled DNAme following Setdb1 knockout (KO) in ground-state and serum-grown mouse embryonic stem cells (ESCs) to illuminate DNAme-dependent and -independent functions of SetDB1. Time-course whole-genome bisulfite sequencing of serum-grown ESCs shows that nearly half of SetDB1 binding sites are enriched with DNAme and H3K9me3, primarily at retrotransposons. Upon Setdb1 KO, both H3K9me3 and DNAme are reduced, with DNAme rapidly removed at many sites by TET enzymes. Some retrotransposons, primarily IAPs, are TET-resistant and lose DNAme slowly via passive dilution. Notably, SetDB1-mediated regulation of H3K27me3, CTCF-binding, and SMAD3 are uncoupled from the DNAme-H3K9me3 axis, and from each other. AlphaFold modeling and co-immunoprecipitation mass spectrometry suggest this uncoupling involves competitive binding to distinct SetDB1 protein domains, highlighting the complex coordination underlying SetDB1 functions.</p>","PeriodicalId":21885,"journal":{"name":"Stem Cell Reports","volume":" ","pages":"103075"},"PeriodicalIF":5.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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