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

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.

KAT3 Shuttling Between Neuronal Identity and Activity-Dependent Plasticity Programs Drives Large-Scale Chromatin Remodeling

ATRX Condensates as Candidate Organizers of Enhancer-Centered Nuclear Microenvironments in Neural Progenitors: A Hypothesis for Enhancer-Associated ATRX Function in Neural Progenitors.

Neural progenitor cells (NPCs) must preserve lineage identity while remaining responsive to developmental cues. Here, we discuss the hypothesis that ATRX condensates help organize enhancer-centered nuclear microenvironments in NPCs. ATRX has long been studied in heterochromatin maintenance, histone variant deposition, and chromatin remodeling; earlier work has also shown that ATRX can occupy euchromatic and active regulatory regions and contribute to transcriptional regulation. Recent evidence in human NPCs indicates that ATRX forms nuclear puncta with condensate-like properties, associates with neurogenic enhancer-rich regions, and incorporates regulatory factors such as CHD7 and p300. Perturbation of ATRX condensate formation is associated with changes in enhancer-associated ATRX occupancy, neural gene-expression programs, and neuroepithelial organization, suggesting a regulatory mode that may complement canonical heterochromatin-associated functions. We propose a dual-mode model in which folded domains contribute to chromatin anchoring at repressive regions, whereas intrinsically disordered regions support condensate-associated organization at active developmental enhancers. We emphasize that whether ATRX condensates activate enhancers de novo, stabilize pre-existing enhancer states, buffer transcriptional variability, or primarily organize cofactor localization remains unresolved. We also discuss limitations of the current evidence and outline acute, locus-specific experiments needed to test the model.

TRIM28 PRESERVES OVARIAN IDENTITY BY STABILIZING LINEAGE-SPECIFIC TRANSCRIPTION FACTOR HUBS

Maintenance of ovarian cell identity is required throughout life to prevent the activation of the testicular program, but the epigenetic mechanisms underlying this process remain poorly understood. Although TRIM28 is required to prevent granulosa-to-Sertoli transdifferentiation, it can act both as a regulator of H3K9me3-dependent heterochromatin and as a transcriptional activator through its E3 SUMOligase activity. Here, we combined CUT&RUN, ATAC-seq and RNA-seq to define the respective contributions of these activities to maintain ovarian cell identity. Strikingly, only a small fraction of TRIM28-bound regions was associated with H3K9me3. Although Trim28 deletion induced focal H3K9me3 loss, it had limited transcriptional consequences and primarily affected repetitive elements rather than regions controlling testis-determining genes. In contrast, Trim28 loss led to reductions in chromatin accessibility and H3K27ac at regions enriched for ovarian transcription factor (TF) motifs FOXL2, NR5A2, ESR2 and RUNX1. Moreover, TRIM28 was frequently co-localized with these TFs on chromatin, and the accessibility and the SUMOylation at these co-bound regions were reduced by Trim28 deletion. Together, our findings identify TRIM28 as a central organizer of ovarian TF hubs whose predominant function is to preserve granulosa cell identity through stabilization of lineage-specific TFs rather than H3K9me3-dependent heterochromatin. GRAPHICAL ABSTRACT

DPF3a couples H3K36me2-dependent chromatin remodeling to genome architecture during myogenesis

The findings uncover a non-canonical mechanism whereby a chromatin remodeler regulates transcription primarily through three-dimensional genome organization rather than local accessibility control, and establish histone modification-guided chromatin remodeling as a key principle in gene regulation.

ERH elicits cell lineage restriction in mammalian preimplantation development and differentiation from pluripotency via H3K9me3-heterochromatin

Enhancer of Rudimentary Homolog (ERH) is an evolutionarily conserved protein originally characterized as promoting fission yeast heterochromatin and recently shown to maintain H3K9me3 heterochromatin in human fibroblasts. Here, we find that ERH depletion in fibroblasts reverts the somatic cell H3K9me3 landscape of broad megabase size domains to an embryonic stem cell (ESC) state composed of mainly H3K9me3 peaks and enables activation of naïve and pluripotency genes and transposable elements during induced pluripotent stem cell (iPSC) reprogramming. Concordantly, we find that ERH represses totipotent and alternative lineage programs during mouse preimplantation development and is required for proper segregation of the inner cell mass and trophectoderm cell lineages. During human ESC differentiation into germ layer lineages, ERH silences naïve and pluripotency genes, transposable elements, and alternative lineage somatic genes. As in fission yeast, we find that mammalian ERH interacts with RNA-binding proteins to engage and repress its chromatin targets. Our findings reveal a conserved, fundamental role for ERH in mammalian cell fate specification via the initiation and maintenance of early developmental gene repression. ERH regulates H3K9me3 to restrict cell lineage. ERH loss reverts H3K9me3 to an ESC-like state, aiding iPSC induction. In mouse blastocysts and hESCs, ERH silences naïve genes, alternative lineages, and transposable elements via RNA-binding cofactors