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This study resolved chromatin ultrastructure during the first lineage decision in mouse and human, separating the pluripotent inner cell mass (ICM) and trophectoderm (TE) states. A dual-tilt chromatin electron tomography method enabled multiscale visualization. TE cells showed denser chromatin with nucleosome aggregation at the nuclear periphery, accompanied by conserved upregulation of Lamin A/C. Lamin A/C loss reduced heterochromatin at the nuclear lamina, reactivated pluripotency genes, and impaired blastocyst expansion and human blastoid formation, defining nucleosome-resolution signatures conserved across early mammalian lineages.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lamin-ac-directs-nucleosome-scale-chromatin-remodeling-to-define-early-lineage-segregation-in-mammals/440618/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lamin-ac-directs-nucleosome-scale-chromatin-remodeling-to-define-early-lineage-segregation-in-mammals/440618.png","ImageObject",300,407,{"name":92,"@type":93},"CatatanPagi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-02","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What biological question does the study address?","Question",{"text":112,"@type":113},"How nucleosome-scale chromatin structure contributes to defining early lineage segregation during mammalian development, specifically between ICM and TE.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What method enables the multiscale chromatin analysis in this work?",{"text":117,"@type":113},"Dual-tilt chromatin electron tomography (2TChromEMT), which supports multiscale visualization of chromatin architecture.",{"name":119,"@type":110,"acceptedAnswer":120},"What happens when Lamin A/C is lost in TE cells?",{"text":121,"@type":113},"Lamin A/C loss reduces heterochromatin at the nuclear lamina, reactivates pluripotency genes, and impairs mouse blastocyst expansion and human blastoid formation.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},440618,1790740701,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","bioRxiv preprint doi: [https://doi.org/10.64898/2026.01.01.696913](https://doi.org/10.64898/2026.01.01.696913); this version posted January 2, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-ND 4.0 International license.  \nLamin A/C directs nucleosome-scale chromatin remodeling to define early lineage segregation in mammals .  \nAlice Sherrard1*\\#, Liangwen Zhong1\\#, Caroline Hoppe1, Srikar Krishna1, Scott Youlten1,2, Curtis W. Boswell1, Stephen Cross3, Fiona E. Sievers1, Goli Ardestani4, Denny Sakkas4, Liyun Miao1, Zachary D. Smith1,5, Berna Sozen1,5,6*, Antonio J. Giraldez1,5,7*  \n1Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT, USA  \n2Current address, Compbiosphere, Agua Blanca, Santa Maria Tonomeca, Oaxaca, Mexico  \n3Wolfson Bioimaging Facility, Biomedical Sciences Building, University of Bristol, Bristol, United Kingdom  \n4Boston IVF-IVIRMA Global Research Alliance, Waltham, MA, USA  \n5Yale Stem Cell Center, Yale University, New Haven, CT, USA  \n6Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, CT, USA  \n7Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA  \n\\# These authors contributed equally to this work  \n* Corresponding authors. Email [antonio.giraldez@yale.edu](antonio.giraldez@yale.edu), [berna.sozen@yale.edu](berna.sozen@yale.edu), [alice.sherrard@yale.edu](alice.sherrard@yale.edu)  \nAbstract: Chromatin organization underlies gene regulation and cell fate specification, yet how nucleosome-scale chromatin structure contributes to lineage segregation during early development remains unknown. Here, we resolved chromatin ultrastructure during the first lineage decision in mouse and human, which forms the pluripotent inner cell mass (ICM) and trophectoderm (TE). To achieve this, we developed dual-tilt chromatin electron tomography (2TChromEMT) that allows multiscale visualization of chromatin architecture. Our analysis reveals that TE cells of both species display denser chromatin with nucleosome aggregation at the nuclear periphery. We show upregulation of the nuclear matrix protein Lamin A/C within the TE lineage across mouse, human, and opossum embryos, indicating that its regulatory role is conserved across eutherian and marsupial species. Loss of Lamin A/C reduces heterochromatin atthe nuclear lamina in TE cells, reactivates pluripotency genes, and impairs mouse blastocyst expansion and human blastoid formation. These findings define the nucleosome-resolution chromatin signatures of early mammalian lineagesand establish Lamin A/C–mediated chromatin organization as a conserved mechanism in the exit from pluripotency and maintenance of trophectoderm identity.  \nT he first lineage decision in mammalian development  \nestablishes the inner cell mass (ICM) and trophectoderm (TE) . These two unique cell lineages display restricted developmental potentials—the ICM exhibits pluripotency and forms the future fetus, and the TE generates the cells that will develop into the placenta1–3. Spatially defined epigenetic and transcriptional programs underlie these cell identities. They are initiated de novo after fertilization and are reinforced by mechanically regulated Hippo signaling4–7, where the nuclear matrix protein Lamin A/C has been implicated in the coupling of mechanical forces to ICM and TE fate8. Pluripotency is established with expression of Nanog, Sox2, and Pou5f1 (Oct4) in ICM precursor cells situated towards the embryo’s interior.  \nIn outer cells that form the TE, Cdx2 and Gata3 repress the pluripotency factors1,3,9–12 . However, whether Lamin A/C directly regulates chromatin structure to drive these gene expression profiles remains unknown.  \nWhile epigenetic marks associated with these cell  \npromotes and stabilizes ICM and T","cbCaivnBHyZm75ye","https://ap.wps.com/l/cbCaivnBHyZm75ye","pdf",9904429,15,"English","# Abstract\n## First lineage decision and chromatin architecture\n## Dual-tilt chromatin electron tomography approach\n## TE-specific nucleosome and nuclear periphery signatures\n## Functional impact of Lamin A/C loss\n## Cross-species conservation and implications","[{\"question\":\"What biological question does the study address?\",\"answer\":\"How nucleosome-scale chromatin structure contributes to defining early lineage segregation during mammalian development, specifically between ICM and TE.\"},{\"question\":\"What method enables the multiscale chromatin analysis in this work?\",\"answer\":\"Dual-tilt chromatin electron tomography (2TChromEMT), which supports multiscale visualization of chromatin architecture.\"},{\"question\":\"What happens when Lamin A/C is lost in TE cells?\",\"answer\":\"Lamin A/C loss reduces heterochromatin at the nuclear lamina, reactivates pluripotency genes, and impairs mouse blastocyst expansion and human blastoid formation.\"}]","Lamin A/C directs nucleosome-scale chromatin remodeling to define early lineage segregation in mammals | PDF",1790692717,38]