Year: 2026
Type: preprint
Abstract: Summary During development, pluripotent stem cells generate diverse cell types through gene regulatory networks orchestrated by combinations of transcription factors (TFs). Following terminal differentiation, however, cellular identities become remarkably stable and resistant to TF-mediated perturbation, yet the mechanisms underlying this stability remain poorly understood. Here, we identify Polycomb repressive complexes (PRCs) as key regulators of neuronal identity maintenance. Although PRCs are well known for repressing the promoters of developmental genes during early cell fate specification, we unexpectedly find that PRC-mediated H3K27me3 expands into megabase-scale domains during neuronal maturation that align with topologically associating domains (TADs). These H3K27me3 “mega-domains” selectively encompass genes associated with alternative neural and non-neural lineages. While depletion of H3K27me3 in mature neurons has only modest effects on basal gene expression, it significantly increases neuronal activity-dependent c-FOS binding and induction of lineage-inappropriate genes within these mega-domains. Our findings reveal a previously unrecognized role for PRCs in establishing TAD-scale repressive chromatin domains during neuronal maturation, thereby safeguarding neuronal identity from external stimuli through broad silencing of alternative cell fate programs.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Secom Science and Technology Foundation, University of Tokyo, Japan Society for the Promotion of Science, RIKEN, International Research Center for Neurointelligence, University of Tokyo, Core Research for Evolutional Science and Technology
Awards: 発生初期における組織特異的エンハンサー確立を介した細胞の運命決定機構の解明, Investigation of the time-dependent Polycomb repression during cellular differentiaion, G253037222, G2942494420, G3680964116, G4572799038, G54601773, G5801289491, 脳表層アストロサイトとは何者なのか（由来・機能の探索）, G7705583931, Elucidation of the mechanisms regulating neural cell fate based on 3D genome structure, Mechanisms underlying developmental establishment of adult neural stem cells and their stress responses
OpenAlex ID: W7202198229