POGZ safeguards neuronal gene chromatin architecture and transcription

Uhrf1 loss disrupts Ctcf-associated chromatin organization during early mouse embryogenesis

UHRF1 is a chromatin-binding protein essential for maintaining DNA methylation and histone modification states, yet its integrated role in vivo remains incompletely understood. To define its function, we generated conditional Uhrf1 knockout embryonic stem cells (ESCs) and embryos. Uhrf1⁻/⁻ ESCs exhibited near-complete loss of 5mC and 5hmC but maintained pluripotency, whereas Uhrf1-null embryos developed normally until E8.5 and then failed to develop further by E9.5, phenocopying Dnmt1 loss. Single-cell multi-omic (ME-seq) profiling of E8.5 embryos revealed impaired lineage stabilization, widespread hypomethylation, and disrupted chromatin architecture. Uhrf1 loss was associated with altered CTCF-associated chromatin signal, broad remodeling of chromatin contacts, altered cis-regulatory relationships, and reduced predicted BMP-related ligand–receptor communication, particularly within neural crest populations. These findings identify Uhrf1 as a central regulator that tightly couples DNA methylation maintenance to 3D genome organization during gastrulation, thereby, directing early lineage specification and positioning Uhrf1 as a pivotal mediator of epigenetic information transfer during early embryogenesis. Highlights Uhrf1 knockout ESCs show global loss of 5mC/5hmC but maintain pluripotency. Uhrf1-null embryos develop normally until E8.5 but die by E9.5 with severe defects. Single-cell multi-omics revealed disrupted chromatin, transcription, and lineage stability upon knockout. Loss of Uhrf1 alters CTCF-associated chromatin signal, predicted BMP-related communication, and cis-regulatory relationships. Graphical abstract

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

Genes that define cell identity are often highly transcribed, but how their activity is regulated to prevent pathological dysregulation remains elusive. Using a two-tiered genetic screen, we identify a network of genes regulating hypertranscribed loci, which is notably enriched for genes mutated in developmental disorders. Among these, ANKRD11, a chromatin regulator haploinsufficient in KBG syndrome, exerts progressively stronger repression on more highly transcribed genes. ANKRD11 enriches around hypertranscribed loci and forms biomolecular condensates via charge-block-patterned intrinsically disordered regions. These condensates spatially sequester elongation factors away from RNA polymerase II, thereby restricting transcription elongation. In mice, Ankrd11 loss abrogates this restriction, causing aberrant developmental gene activation, disrupted organogenesis, and embryonic lethality. Critically, KBG patient cells with ANKRD11 mutations show defective condensate formation and consequent overactivation of hypertranscribed genes. These results uncover a condensate-mediated mechanism that restricts hypertranscribed genes and suggest its disruption underlies developmental disorders such as KBG syndrome.

The linker histone H1.4 condenses chromatin in maturing postmitotic neurons

H1 histones are abundant nuclear proteins that bind to linker DNA at the entry and exit points of nucleosomes. Although individual H1 family members play partially redundant roles in chromatin organization, the discovery of disease-associated mutations in H1 genes has raised interest in their cell-type specific functions. Heterozygous, de novo frameshift mutations in H1-4 cause the neurodevelopmental disorder Rahman Syndrome, which is characterized by mild to severe intellectual disability along with other neurological and morphological features. H1.4 has mostly been studied in dividing cells, and its expression in the brain was poorly understood. Here we characterized the expression of H1f4 mRNA and H1.4 protein in the brains of male and female mice across postnatal development. Using an epitope-tagged H1f4 knockin mouse, we show that this linker histone is robustly expressed throughout the brain including in mature, post-mitotic neurons of adult mice. By chromatin immunoprecipitation, we observe that H1.4 binds broadly across the genome in neural progenitors and accumulates in heterochromatin over the course of neuronal maturation. Finally we show that developmental maturation of chromatin compaction in cerebellar granule neurons is disrupted in H1f2/H1f4 double knockout mice. These data raise the possibility that the neurological changes in Rahman Syndrome may arise from disrupted functions of histone H1.4 in neurons.

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

The nuclear RNA exosome, a conserved 3′→5′ ribonuclease complex, degrades the vast majority of RNA polymerase II output, including promoter upstream transcripts, enhancer RNAs, antisense transcripts, and retrotransposon-derived RNAs. Beyond this housekeeping role, the exosome acts as an epigenetic effector, and its dysfunction underlies a growing spectrum of human disease. Here we integrate recent structural, genomic, and disease-focused studies into a unified model of the exosome as a guardian of the epigenome. We describe how MTR4-containing adaptor complexes TRAMP, NEXT, and PAXT confer substrate selectivity, and how the exosome enforces heterochromatic silencing in concert with HP1 proteins and the Human Silencing Hub (HUSH) complex and preserves three-dimensional genome architecture at insulators and enhancers, such as the protocadherin locus where RNA surveillance, CTCF insulation, and heterochromatin converge. We then examine the consequences of failure: exosomopathies such as pontocerebellar hypoplasia, loss of DIS3- and PAXT-mediated tumor suppression in cancer, and age-related erosion of surveillance that permits transposable element de-repression, RIG-1/MDA5 and cGAS-STING-driven inflammation, cellular senescence, and neurodegeneration. We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.

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

MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder.

Functional modelling in zebrafish confirms a loss‑of-function mechanism and highlights species‑dependent differences specifically in the impact of the missense variant on protein function, and provides a cautionary tale about overreliance on animal models as a screening tool for variant classification.