The conserved N-terminal SANT1-binding domain (SBD) of EZH2 Regulates PRC2 Activity DOI Open Access
Agata L. Patriotis, Yadira M. Soto-Feliciano, Douglas Barrows

et al.

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

Alternative splicing decouples local from global PRC2 activity DOI Creative Commons

Niccolò Arecco,

Ivano Mocavini, Enrique Blanco

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(6), P. 1049 - 1061.e8

Published: March 1, 2024

The Polycomb repressive complex 2 (PRC2) mediates epigenetic maintenance of gene silencing in eukaryotes via methylation histone H3 at lysine 27 (H3K27). Accessory factors define two distinct subtypes, PRC2.1 and PRC2.2, with different actions chromatin-targeting mechanisms. mechanisms orchestrating PRC2 assembly are not fully understood. Here, we report that alternative splicing (AS) core component SUZ12 generates an uncharacterized isoform SUZ12-S, which co-exists the canonical SUZ12-L virtually all tissues developmental stages. SUZ12-S drives formation favors dimerization. While is necessary sufficient for repression target genes promoter-proximal H3K27me3 deposition, maintains global H3K27 levels. Mouse embryonic stem cells (ESCs) lacking either exit pluripotency more slowly fail to acquire neuronal cell identity. Our findings reveal a physiological mechanism regulating higher-order interactions eutherians, impacts on repression.

Language: Английский

Citations

11
Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications DOI Creative Commons
Trinity Cookis,

Alexandria Lydecker,

Paul Sauer

et al.

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Abstract Polycomb repressive complex 2 (PRC2) trimethylates histone H3 on K27 (H3K27me3) leading to gene silencing that is essential for embryonic development and maintenance of cell identity. PRC2 regulated by protein cofactors their crosstalk with modifications. Trimethylated K4 (H3K4me3) K36 (H3K36me3) localize sites active transcription inhibit activity through unknown mechanisms. Using cryo-electron microscopy, we reveal tails containing H3K36me3 engage poorly preclude its effective interaction chromatin, while H3K4me3 binds the allosteric site in EED subunit, acting as an antagonist competes activators required spreading H3K27me3 mark. Thus, location modifications along tail allows them target two requirements efficient trimethylation H3K27 PRC2. We further show JARID2 cofactor modulates presence these

Language: Английский

Citations

1
Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications DOI Creative Commons
Trinity Cookis,

Alexandria Lydecker,

Paul Sauer

et al.

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

Published: Feb. 10, 2024

Summary Polycomb repressive complex 2 (PRC2) is an epigenetic regulator essential for embryonic development and maintenance of cell identity that trimethylates histone H3 at lysine 27 (H3K27me3) leading to gene silencing. PRC2 regulated by association with protein cofactors crosstalk posttranslational modifications. Trimethylated K4 (H3K4me3) K36 (H3K36me3) localize sites active transcription where H3K27me3 absent inhibit activity through unknown mechanisms. Using cryo-electron microscopy we reveal tails modified H3K36me3 engage poorly the site preclude its effective interaction chromatin, while H3K4me3 modification binds allosteric in EED subunit, acting as antagonist competes activators required spreading mark. Thus, location along tail modifications allow them target two requirements efficient trimethylation H3K27. We further show JARID2 cofactor modulates presence these

Language: Английский

Citations

4
The conserved N-terminal SANT1-binding domain (SBD) of EZH2 Regulates PRC2 Activity DOI Open Access
Agata L. Patriotis, Yadira M. Soto-Feliciano, Douglas Barrows

et al.

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

Citations

0