Abstract
In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated an Uhrf1 knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygous Uhrf1 KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences. In vitro UHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications. We also show that the nucleosome positioning affects the binding of methylated DNA by UHRF1. Thus, while our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.
Highlights
In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation
Methylation pathways are dependent on H3K9 methylation[1,10,47,48], DNA maintenance methylation in mammalian cells by UHRF1-DNMT1 axis, which is responsible for majority of DNA methylation in mammalian cells is, to a large extent, independent on H3K9 methylation
In Neurospora, DNA methylation is strictly dependent on H3K9 methylation because the DNA methyltransferase DIM-2 is recruited to chromatin by its interaction with a HP1-like protein, which binds chromatin via binding H3K9me[2] generated by H3K9 methyltransferase DIM-5
Summary
In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Studies from Neurospora have demonstrated that in this model organism the DNA methylation catalysed by DIM-2 is strictly dependent on a histone H3K9 methyltransferase DIM-5 (refs 10,11). Three active DNA methyltransferases DNMT3A, DNMT3B and DNMT1 are responsible for all known CG and non-CG methylation in mammals[3,17]. DNMT3A and DNMT3B form complexes with enzymatically inactive DNMT3L and play critical roles in establishment of patterns of DNA methylation during gametogenesis and early embryonic development. On the basis of the unique property of SRA, UHRF1 was initially proposed to recruit DNMT1 to replication forks by binding hemi-methylated CpGs generated during DNA replication[23,24].
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