Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase.

Abstract:

:Cytosine methylation of genomic DNA controls gene expression and maintains genome stability. How a specific DNA sequence is targeted for methylation by a methyltransferase is largely unknown. Here, we show that histone H3 tails lacking lysine 4 (K4) methylation function as an allosteric activator for methyltransferase Dnmt3a by binding to its plant homeodomain (PHD). In vitro, histone H3 peptides stimulated the methylation activity of Dnmt3a up to 8-fold, in a manner reversely correlated with the level of K4 methylation. The biological significance of allosteric regulation was manifested by molecular modeling and identification of key residues in both the PHD and the catalytic domain of Dnmt3a whose mutations impaired the stimulation of methylation activity by H3 peptides but not the binding of H3 peptides. Significantly, these mutant Dnmt3a proteins were almost inactive in DNA methylation when expressed in mouse embryonic stem cells while their recruitment to genomic targets was unaltered. We therefore propose a two-step mechanism for de novo DNA methylation - first recruitment of the methyltransferase probably assisted by a chromatin- or DNA-binding factor, and then allosteric activation depending on the interaction between Dnmt3a and the histone tails - the latter might serve as a checkpoint for the methylation activity.

journal_name

Cell Res

journal_title

Cell research

authors

Li BZ,Huang Z,Cui QY,Song XH,Du L,Jeltsch A,Chen P,Li G,Li E,Xu GL

doi

10.1038/cr.2011.92

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

1172-81

issue

8

eissn

1001-0602

issn

1748-7838

pii

cr201192

journal_volume

21

pub_type

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