Condensates of the chromatin regulator ANKRD11 restrict hypertranscribed genes to safeguard development.

Intrinsically disordered regions restrain genomic targeting of RNA and histone demethylases in mammals and plants

Polycomb establishes TAD-scale H3K27me3 mega-domains to safeguard neuronal identity

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. Graphical Abstract

Plant LHP1 as a Context‐Dependent Regulator of Polycomb‐Associated Chromatin

Like heterochromatin protein 1 (LHP1) is a conserved HP1‐like chromatin protein in land plants and a major Polycomb‐associated factor that recognizes H3K27me3 enriched euchromatic domains. Recent biochemical, genomic, and structural studies show that LHP1 acts as a modular chromatin scaffold whose regulatory output depends on local histone modifications, RNA interactions, transcriptional factors, and PRC1/PRC2‐associated partners. In this review, we outline emerging roles of LHP1 in Polycomb‐mediated repression, chromatin‐state maintenance, transcriptional responsiveness, hormone signaling, stress responses, and TE‐proximal gene regulation. We also examine the structural features and evolutionary diversification of LHP1 homologs across land plants and assess how duplicated LHP1 copies may contribute to species‐specific developmental and stress‐adaptive traits. Rather than presenting LHP1 as a universal master regulator, we emphasize its context‐dependent functions and distinguish experimentally supported mechanisms from correlative or still unresolved models. Finally, we highlight future directions involving genome editing, epigenomic profiling, chromatin conformation analysis, and targeted epigenome engineering to clarify how LHP1 associated modules may be exploited for crop improvement and postharvest quality management.

AIRE transcriptional condensates in central tolerance: a multiscale mechanistic perspective

Autoimmune regulator (AIRE) enables medullary thymic epithelial cells (mTECs) to express a broad but selective repertoire of tissue-restricted antigens (TRAs), thereby supporting central T-cell tolerance. Recent studies showing that AIRE forms transcriptionally active condensates provide a framework for understanding how chromatin recognition, enhancer-associated cofactor recruitment, three-dimensional genome organization and transcriptional elongation are coordinated during TRA induction. In this view, sparse TRA expression reflects the low probability that a given locus reaches a permissive chromatin and cofactor state, whereas high output may result from local enrichment of BRD4, P-TEFb, Mediator-associated co-activators and elongation machinery after activation. Recent findings on thymic mimetic cells, human thymic spatial organization and peripheral RORγt-associated antigen-presenting cells are discussed as related contexts, with particular attention to the current lack of direct evidence for mTEC-like AIRE condensate mechanisms outside mTECs. Together, these studies place AIRE condensates within a broader regulatory landscape of chromatin gating, transcriptional kinetics and mTEC state diversity.

Cohesin and NuRD antagonistically drive alternative neuronal fates via PLZF transcription factors

Diverse genetic and epigenetic factors cooperate to specify cellular fates during development. Establishing these fates is especially critical in the nervous system, which comprises diverse neuronal cell types. How genomic architecture interfaces with epigenetic regulators to drive transcriptional programs underlying neuronal fates remains poorly understood. Here, we show that cohesin, a protein complex that shapes genomic architecture, promotes GABAergic fate specification in a subset of neurons in the nematode Caenorhabditis elegans. This process is facilitated by EOR-1, a homolog of the human promyelocytic leukemia zinc finger (PLZF) transcription factor. The nucleosome remodeling and deacetylase (NuRD) complex and TRA-4, another PLZF homolog, promote tyraminergic fate in the normally GABAergic neurons when cohesin or EOR-1 function is lost, revealing an antagonistic mechanism determining alternative neuronal fates. These findings highlight a critical interplay among genome architecture, epigenetic remodeling, and transcriptional regulation in neuronal fate specification and, given the evolutionary conservation of these factors, suggest a mechanism underlying neural development across species.

HUSH, NEXT PROMPT: Epigenetics and the Nuclear RNA Exosome in Human Aging and Disease

It is concluded that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.