Acquired Tissue-Specific Promoter Bivalency Is a Basis for PRC2 Necessity in Adult Cells

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From: Cell(Vol. 165, Issue 6)
Publisher: Elsevier B.V.
Document Type: Article
Length: 382 words

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To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.cell.2016.04.031 Byline: Unmesh Jadhav (1,2,3), Kodandaramireddy Nalapareddy (1,2,3), Madhurima Saxena (1,2,3), Nicholas K. O'Neill (1), Luca Pinello (4,5), Guo-Cheng Yuan (4,5,6), Stuart H. Orkin (6,7,8,9), Ramesh A. Shivdasani [ramesh_shivdasani@dfci.harvard.edu] (1,2,3,6,*) Highlights * Distinct groups of promoters in adult tissues carry both H3K4me3 and H3K27me3 marks * Tissue-specific H3K27me3 appears late in development and keeps genes silent * Many other genes with stable or dynamic H3K27me3 are unaffected by loss of this mark * Bivalent genes are derepressed in PRC2 null cells in proportion to H3K4me3 levels Summary Bivalent promoters in embryonic stem cells (ESCs) carry methylation marks on two lysine residues, K4 and K27, in histone3 (H3). K4me2/3 is generally considered to promote transcription, and Polycomb Repressive Complex 2 (PRC2) places K27me3, which is erased at lineage-restricted genes when ESCs differentiate in culture. Molecular defects in various PRC2 null adult tissues lack a unifying explanation. We found that epigenomes in adult mouse intestine and other self-renewing tissues show fewer and distinct bivalent promoters compared to ESCs. Groups of tissue-specific genes that carry bivalent marks are repressed, despite the presence of promoter H3K4me2/3. These are the predominant genes de-repressed in PRC2-deficient adult cells, where aberrant expression is proportional to the H3K4me2/3 levels observed at their promoters in wild-type cells. Thus, in adult animals, PRC2 specifically represses genes with acquired, tissue-restricted promoter bivalency. These findings provide new insights into specificity in chromatin-based gene regulation. Author Affiliation: (1) Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA (2) Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA (3) Department of Medicine, Harvard Medical School, Boston, MA 02215, USA (4) Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA (5) Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA (6) Harvard Stem Cell Institute, Cambridge, MA 02138, USA (7) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA (8) Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA (9) Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115, USA * Corresponding author Article History: Received 18 December 2015; Revised 23 February 2016; Accepted 8 April 2016 (miscellaneous) Published: May 19, 2016

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Gale Document Number: GALE|A521660385