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

Disruption of Histone H4C genes impairs skeletal development and cortical neurogenesis, modeling rare neurodevelopmental syndromes

Histone proteins, which reside in the nuclei of eukaryotic cells, are involved in diverse cellular processes. The core histone H4 serves as a structural component of the nucleosome. Patients carrying mutations in H4Clustered histone (H4C) genes exhibit a broad spectrum of developmental abnormalities, including short stature, microcephaly, intellectual disability, growth retardation, and digital anomalies. However, the impact of H4 mutations on mammalian embryogenesis remains largely unclear. Here, we demonstrate that histone H4C genes play crucial roles in skeletal development and cortical neurogenesis. We found that mRNAs of the histone H4C gene family are specifically expressed in proliferating progenitor cells in the developing mouse neocortex and in human induced pluripotent stem cell-derived cortical organoids. CRISPR-mediated disruption of H4C3 in mice caused severe defects in skeletal formation and neocortical neurogenesis. Furthermore, overexpression of a mutant form of H4C3 resulted in altered expression of genes associated with cellular migration and motility. Together, these findings suggest that histone H4 plays a critical role in regulating the balance between proliferation and differentiation during mammalian embryonic development, thereby explaining the broad spectrum of patient phenotypes.

Reading the maps: Organization and function of chromatin types in Drosophila

Are components of the histone gene expression machinery functionally repurposed in terminally differentiated cells?

The expression of metazoan replication-dependent histone genes is controlled by NPAT and U7 snRNP. NPAT activates transcription of histone genes during S-phase, whereas U7 snRNP is a multi-subunit endonuclease that cleaves the resultant transcripts at the 3' end, yielding mature histone mRNAs. In cycling cells, NPAT and U7 snRNP with its four unique components, U7 snRNA, Lsm10, Lsm11 and FLASH, are highly enriched in Histone Locus Bodies (HLBs), nuclear condensates formed near histone gene loci. Here, we show that in muscle and neural cells that have ceased to replicate their chromatin and permanently exited the cell cycle, HLBs are dismantled and NPAT, FLASH and Lsm11 are detected in the cytoplasm. This observation suggests that in postmitotic cells, NPAT and U7 snRNP become repurposed for functions unrelated to generating histone mRNAs. We identified a highly conserved region in Lsm11 that engages in various protein-protein interactions and likely acts as a universal platform that controls the assembly, localization and function of Lsm11 complexes, including U7 snRNP, during cell growth and differentiation. Since the assembly of U7 snRNP requires SMN, the protein mutated in spinal muscular atrophy (SMA), our results may provide a new perspective on pathophysiology of this neuromuscular disorder.

Dynamic networks of intrinsically disordered regions in nuclear proteins

Chromatin in the eukaryotic nucleus is organized into transcriptionally active euchromatin and transcriptionally silent heterochromatin. Its fundamental unit, the nucleosome, consists of two copies each of histones H2A, H2B, H3, and H4 wrapped by ~145 base pairs of DNA, flanked by linker-DNA that binds linker-histone H1 to form a chromatosome. In euchromatin, histone N-terminal tails (N-tails) are extensively acetylated. In facultative heterochromatin, H3K27 is methylated (H3K27me) and the H2A C-terminal tail (C-tail) is ubiquitinated (H2Aub), whereas in constitutive heterochromatin, H3K9 is methylated (H3K9me) and recognized by heterochromatin protein 1 (HP1). The N-tail of the HP1α homologue is phosphorylated, enhancing its binding to H3K9me and promoting liquid–liquid phase separation (LLPS). In addition, the C-tails of the histone chaperones FACT and NAP1 mediate binding to H2A-H2B. These N-tails and C-tails are intrinsically disordered regions (IDRs), whose dynamic conformations are accessible primarily through NMR spectroscopy. NMR has revealed dynamic IDR interaction networks essential for chromatin regulation, including H3 N-tail acetylation enhanced by H4 N-tail acetylation on linker-DNA, its suppression by H1, H3K27 methylation promoted by H2Aub, H3 N-tail acetylation induced by phosphorylated FACT C-tail, the role of the NAP1 C-tail in H2A-H2B binding, and phosphorylation-dependent enhancement of HP1 N-tail binding to H3K9me and LLPS. Thus, NMR has illuminated how dynamic interactions among nuclear IDRs play central roles in establishing euchromatin and heterochromatin, providing insights into the molecular basis of nuclear function.

Linker Histones: The Multiple Binding Modes of the Enigmatic 5th Histone

Chromatin structure is dynamic and regulated by many factors, including enzymes that chemically modify histones and DNA, chromatin remodeling complexes that physically manipulate nucleosomes and chromatin, and non-enzymatic proteins that bind to DNA or nucleosomes to create specialized regions in chromatin. This multifactorial regulation stems from the need for fine-tuned control, which is key in processes including DNA repair, replication, and gene expression. Linker histones are a family of proteins structurally distinct from the core histones that provide a poorly understood layer of regulation in chromatin. In this review, we introduce the basics of chromatin structure, what is known about how linker histones (H1s) bind to nucleosomes and influence chromatin, and how the individual domains within H1s contribute to these activities. We especially focus on recent studies describing canonical and alternative H1-nucleosome binding and their potential roles in chromatin.

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

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.