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An epigenetic switch regulates de novo DNA methylation at pluripotency gene enhancers
Author(s) -
Gowher Humaira,
Petell Christopher J
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.593.15
Subject(s) - epigenetics , histone , histone methylation , enhancer , epigenomics , chromatin , histone code , ezh2 , histone methyltransferase , biology , microbiology and biotechnology , dna methylation , chemistry , genetics , dna , gene expression , gene , nucleosome
Structural studies have shown that the chromatin binding ADD domain of Dnmt3a interacts specifically with the unmethylated histone H3K4 (H3K4me0) which relieves the Dnmt3a enzyme from its auto‐inhibited state. We suggest this interaction has the potential to function as a dynamic regulatory switch in which histone demethylation events act as signals to locally activate Dnmt3 enzymes. Active enhancers are marked by the presence of histone H3K4 monomethylation and H3K27 acetylation. During ESC differentiation, Lsd1‐Mi2/NURD complex removes histone H3K4 monomethylation and histone acetylation specifically at the pluripotency gene enhancer (Whyte et. al, 2012). Depicted in the illustration, our data here shows that this activity Lsd1‐Mi2/NURD at pluripotency gene enhancers activates Dnmt3a enzyme, causing site‐specific DNA methylation that is important for the stable repression of pluripotency genes. We show Dnmt3a functions as a reader and effector in this queue of epigenetic events, where local histone deacetylation and demethylation allows the specific activation of Dnmt3a through the interaction of Dnmt3a ADD with demethylated histone tails causing local DNA methylation; thereby locking PpG enhancers in a stable repressive state.