UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9

Abstract

Epigenetic inheritance of DNA methylation in mammals requires a multifunctional protein UHRF1, which is believed to recruit DNMT1 to DNA replication forks through a unique hemi-methylated CpG-binding activity. Here we demonstrate that the UHRF1 mutants deficient in binding either hemi-methylated CpG or H3K9me2/3, but not both, are able to associate with pericentric heterochromatin, recruit Dnmt1 and partially rescue DNA methylation defects in mouse Uhrf1 null ES cells. Furthermore, we present evidence that the flip out of the methylated cytosine induced by UHRF1 binding is unlikely essential for subsequent DNA methylation by DNMT1. Together, our study demonstrates that UHRF1 can target DNMT1 for DNA maintenance methylation through binding either H3K9me2/3 or hemi-methylated CpG, and that the presence of both binding activities ensures high fidelity DNA maintenance methylation. In addition, our study indicates that UHRF1 mediates cross-talk between H3K9 methylation and DNA methylation at the level of DNA methylation maintenance.

Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation

“…As such, UHRF1 is one of a few proteins known to recognize both histone and DNA regulatory marks on chromatin. Unpublished findings from our laboratory and recent work by Liu et al (2013) suggest an important role for SRA binding in cells, and careful examination of this apparent multivalent interaction with histones and DNA will be an important area of future biochemical study.…”

E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation

“…Uhrf1 is a molecule previously reported to be expressed in OPCs (Dugas et al, 2006). In proliferating cells it binds to hemi-methylated DNA and has been proposed to couple methylation of DNA to histone methylation (Hashimoto et al, 2010;Liu et al, 2013), and has been implicated as a regulator of the fidelity to accurately transmit DNA methylation during the process of DNA replication (Bostick et al, 2007;Sharif et al, 2007;Arita et al, 2008;Avvakumov et al, 2008;Zhang et al, 2011).…”

“…They include a wide spectrum of malignancies ranging from slow-growing to highly aggressive tumors (Louis et al, 2007). A critical property of tumor cells is their loss of the ability to properly respond to the environmental cues, thus deregulating the mechanisms of proliferation and differentiation.…”

How to make a primordial germ cell

“…This induction, together with the repression of Ehmt1, ensures rapid and global loss of H3K9me2, and could account for the re-expression of pluripotency genes and promote DNA demethylation (Liu et al, 2013;Rothbart et al, 2012). The repression of Kdm6b demethylase by PRDM14 and BLIMP1 contributes to the global increase in H3K27me, which is also seen in the inner cell mass of blastocysts.…”