Engineering of a histone-recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs Journal Article


Authors: Noh, K. M.; Wang, H.; Kim, H. R.; Wenderski, W.; Fang, F.; Li, C. H.; Dewell, S.; Hughes, S. H.; Melnick, A. M.; Patel, D. J.; Li, H.; Allis, C. D.
Article Title: Engineering of a histone-recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs
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 tohistone 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. © 2015 Elsevier Inc.
Journal Title: Molecular Cell
Volume: 59
Issue: 1
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2015-07-02
Start Page: 89
End Page: 103
Language: English
DOI: 10.1016/j.molcel.2015.05.017
PROVIDER: scopus
PMCID: PMC4491196
PUBMED: 26073541
DOI/URL:
Notes: Export Date: 3 August 2015 -- Source: Scopus
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  1. Dinshaw J Patel
    479 Patel