Navigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(18), P. 3381 - 3405

Published: Aug. 23, 2024

Language: Английский

---

The conserved N-terminal SANT1-binding domain (SBD) of EZH2 Regulates PRC2 Activity

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Abstract Polycomb group proteins maintain gene expression patterns established during early development, with Repressive Complex 2 (PRC2) methyltransferase a key regulator of cell differentiation, identity and plasticity. Consequently, extensive somatic mutations in PRC2, including gain- or loss- function (GOF LOF), are observed human cancers. The regulation chromatin structure by PRC2 is critically dependent on its EZH2 (Enhancer Zeste Homolog 2) subunit, which catalyzes the methylation histone H3 lysine 27 (H3K27). Recent structural studies revealed conformational changes non-catalytic N-terminal SANT-Binding Domain (SBD) activation, though functional significance remains unclear. Here, we investigate how SBD regulates function. domain highly conserved metazoans, dispensable for assembly localization, yet required genome-wide H3K27 methylation. Further, show that an intact necessary proliferation EZH2- addicted lymphomas, deletion presence GOF inhibits cancer growth. These observations provide new insights to activity normal development malignancy.

Language: Английский

---

Histone deacetylase-1 is required for epigenome stability in Neurospora crassa

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 20, 2025

Abstract Polycomb group (PcG) proteins form chromatin modifying complexes that stably repress lineage- or context-specific genes in animals, plants, and some fungi. Repressive Complex 2 (PRC2) catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3) to assemble repressive chromatin. In the model fungus Neurospora crassa, H3K27me3 deposition is controlled by H3K36 methyltransferase ASH1 components constitutive heterochromatin including H3K9me3-binding protein HETEROCHROMATIN PROTEIN 1 (HP1). Hypoacetylated histones are a defining feature both PcG-repressed chromatin, but how deacetylases (HDACs) contribute normal transcriptional repression within poorly understood. We performed genetic screen identify HDACs required for PRC2-methylated genes. absence HISTONE DEACETYLASE-1 (HDA-1), were activated was depleted from typical PRC2-targeted regions. At heterochromatin, HDA-1 deficient cells displayed reduced H3K9me3, hyperacetylation, aberrant enrichment H3K36me3. CHROMODOMAIN PROTEIN-2 (CDP-2) target also patterns. Patterns distinct isogenic Δ hda-1 strains, suggesting loss causes stochastic progressive epigenome dysfunction. To test this, we constructed new Δhda-1 strain laboratory evolution experiment. Deletion led decay over hundreds nuclear divisions. Together, our data indicate critical regulator stability N. crassa .

Language: Английский

---

Dual roles of histone H3 lysine-4 in antagonizing Polycomb group function and promoting target gene expression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 29, 2024

Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb trithorax complexes determine the ON/OFF state targets like Hox genes. Trithorax encodes a methyltransferase specific to histone H3 lysine-4 (H3K4). However, there no direct evidence that H3K4 regulates group target genes

Language: Английский

---