| Literature DB >> 26073541 |
Kyung-Min Noh1,2, Haibo Wang3,4, Hyunjae R Kim5, Wendy Wenderski1, Fang Fang6, Charles H Li1, Scott Dewell7, Stephen H Hughes8, Ari M Melnick6, Dinshaw J Patel9, Haitao Li3,4,10, C David Allis1.
Abstract
Histone modification and DNA methylation are associated with varying epigenetic "landscapes," but detailed mechanistic and functional links between the two remain unclear. Using the ATRX-DNMT3-DNMT3L (ADD) domain of the DNA methyltransferase Dnmt3a as a paradigm, we apply protein engineering to dissect the molecular interactions underlying the recruitment of this enzyme to specific regions of chromatin in mouse embryonic stem cells (ESCs). By rendering the ADD domain insensitive to histone modification, specifically H3K4 methylation or H3T3 phosphorylation, we demonstrate the consequence of dysregulated Dnmt3a binding and activity. Targeting of a Dnmt3a mutant to H3K4me3 promoters decreases gene expression in a subset of developmental genes and alters ESC differentiation, whereas aberrant binding of another mutant to H3T3ph during mitosis promotes chromosome instability. Our studies support the general view that histone modification "reading" and DNA methylation are closely coupled in mammalian cells, and suggest an avenue for the functional assessment of chromatin-associated proteins.Entities:
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Year: 2015 PMID： 26073541 PMCID： PMC4491196 DOI： 10.1016/j.molcel.2015.05.017
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970