Polycomb establishes TAD-scale H3K27me3 mega-domains to safeguard neuronal identity
- 1The University of Tokyo
Abstract
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.
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BibTeX
@misc{yamada2026polycomb,
title = {{Polycomb establishes TAD-scale H3K27me3 mega-domains to safeguard neuronal identity}},
author = {N. Yamada and C. Ichihara and K. Hojo and K. Oishi and H. Sugishita and Y. Gotoh},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.10.743812},
url = {https://www.biorxiv.org/content/10.64898/2026.08.10.743812v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Polycomb establishes TAD-scale H3K27me3 mega-domains to safeguard neuronal identity
AU - N. Yamada
AU - C. Ichihara
AU - K. Hojo
AU - K. Oishi
AU - H. Sugishita
AU - Y. Gotoh
PY - 2026
DA - 2026/08/10
PB - bioRxiv
DO - 10.64898/2026.08.10.743812
UR - https://www.biorxiv.org/content/10.64898/2026.08.10.743812v2
AB - 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.
ER -