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Cell. 2016 Jun 2;165(6):1389-1400. doi: 10.1016/j.cell.2016.04.031. Epub 2016 May 19.

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

Author information

1
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
2
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
4
Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
5
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Children's Hospital, Boston, MA 02115, USA.
6
Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: ramesh_shivdasani@dfci.harvard.edu.

Abstract

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.

PMID:
27212235
PMCID:
PMC4893000
DOI:
10.1016/j.cell.2016.04.031
[Indexed for MEDLINE]
Free PMC Article

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