Polycomb group proteins (PcGs) drive target gene repression and form large chromatin domains. In , DNA elements known as Polycomb group response elements (PREs) recruit PcGs to the DNA. We have shown that, within the (-) Polycomb domain, strong, constitutive PREs are dispensable for Polycomb domain structure and function. We suggest that the endogenous chromosomal location imparts stability to this Polycomb domain. To test this possibility, a 79-kb transgene was inserted into other chromosomal locations. This transgene is functional and forms a Polycomb domain. The spreading of the H3K27me3 repressive mark, characteristic of PcG domains, varies depending on the chromatin context of the transgene. Unlike at the endogenous locus, deletion of the strong, constitutive PREs from the transgene leads to both loss- and gain-of function phenotypes, demonstrating the important role of these regulatory elements. Our data show that chromatin context plays an important role in Polycomb domain structure and function.
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http://dx.doi.org/10.1126/sciadv.aau9739 | DOI Listing |
Cell
January 2025
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address:
Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome.
View Article and Find Full Text PDFNat Struct Mol Biol
January 2025
Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
The compaction of chromatin is a prevalent paradigm in gene repression. Chromatin compaction is commonly thought to repress transcription by restricting chromatin accessibility. However, the spatial organization and dynamics of chromatin compacted by gene-repressing factors are unknown.
View Article and Find Full Text PDFDevelopment
January 2025
Department of Histology and Cell Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
JCI Insight
December 2024
Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.
Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and genes repression. EZH2 is overexpressed in many cancers and studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in PDAC patients is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression.
View Article and Find Full Text PDFMol Cell
December 2024
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK. Electronic address:
Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state.
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