287: EPOP and MTF2 modulate PRC2 H3K27me3 deposition via GA- and GCN-sequence specificity

Granata J et al., Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2527303123 - In mESCs and defined in vitro assays, EPOP and MTF2 stimulate PRC2 methyltransferase activity and promote de novo H3K27me3 deposition with GA- or GCN-rich DNA preference. Key terms: EPOP, MTF2, PRC2, H3K27me3, DNA-sequence specificity.

Study Highlights:
The study used mouse embryonic stem cells with an EED-rescue system and recombinant in vitro assays including HMT assays, EMSA, and ChIP-seq to probe EPOP and MTF2 function. Biochemical HMT assays on oligonucleosomes and dinucleosomes show both EPOP and MTF2 directly stimulate PRC2 catalytic activity, with MTF2 preferentially enhancing activity and binding on GCN-rich linkers and EPOP on GA-rich linkers. ChIP-seq during EED rescue demonstrated that EPOP is dispensable for initial PRC2 recruitment but its knockout reduces de novo H3K27me3 deposition by ~50% and cooperates with MTF2 and JARID2. Together these data indicate linker DNA sequence within nucleation sites guides subcomplex-specific PRC2 binding and catalytic output, influencing spatial establishment of H3K27me3 domains.

Conclusion:
EPOP and MTF2 define distinct PRC2 subcomplexes that stimulate PRC2 catalytic activity in a chromatin-dependent, DNA-sequence-specific manner to direct de novo H3K27me3 deposition.

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Article title:
EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity

First author:
Granata J

Journal:
Proc. Natl. Acad. Sci. U.S.A. 2026.123:e2527303123

DOI:
10.1073/pnas.2527303123

Reference:
Granata J., Liu S., Popoca L., Oksuz O., Reinberg D. EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2527303123. https://doi.org/10.1073/pnas.2527303123

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript segments describing PRC2 function, EPOP/MTF2 cofactors, in vitro histone methyltransferase (HMT) assays, the EED rescue system and de novo recruitment, dinucleosome substrates with GA- and GCN-rich linker DNA, EMSA binding data, and the rheostat model of cofactors shaping genome-wide H3K27me3 pattern
- transcript topics: PRC2 function and H3K27me3 deposition; EPOP and MTF2 as PRC2 cofactors; In vitro PRC2 histone methyltransferase assays; EED rescue system and de novo PRC2 recruitment; Dinucleosome substrates with GA- and GCN-rich linker DNA; EMSA nucleosome binding and affinity

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- EPOP and MTF2 stimulate PRC2 histone methyltransferase (HMT) activity in vitro
- EPOP is dispensable for de novo PRC2 recruitment; MTF2 is essential for de novo recruitment
- EPOP knockout reduces de novo H3K27me3 deposition in vivo by ~5...