title: Acquired Tissue-Specific Promoter Bivalency Is a Basis for PRC2 Necessity in Adult Cells.
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.
authors.affiliation: 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.
authors.forename: Unmesh
authors.initials: U
authors.lastname: Jadhav
authors.affiliation: 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.
authors.forename: Kodandaramireddy
authors.initials: K
authors.lastname: Nalapareddy
authors.affiliation: 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.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Saxena
authors.affiliation: Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: O'Neill
authors.affiliation: 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.
authors.forename: Luca
authors.initials: L
authors.lastname: Pinello
authors.affiliation: 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.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: 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.
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: D006657:Histones; D063151:Polycomb Repressive Complex 2; D008239:Lysine