Abstract
UHRF2 has been implicated as a novel regulator for both DNA methylation (5mC) and hydroxymethylation (5hmC), but its physiological function and role in DNA methylation/hydroxymethylation are unknown. Here we show that in mice, UHRF2 is more abundantly expressed in the brain and a few other tissues. Uhrf2 knock-out mice are viable and fertile and exhibit no gross defect. Although there is no significant change of DNA methylation, the Uhrf2 null mice exhibit a reduction of 5hmC in the brain, including the cortex and hippocampus. Furthermore, the Uhrf2 null mice exhibit a partial impairment in spatial memory acquisition and retention. Consistent with the phenotype, gene expression profiling uncovers a role for UHRF2 in regulating neuron-related gene expression. Finally, we provide evidence that UHRF2 binds 5hmC in cells but does not appear to affect the TET1 enzymatic activity. Together, our study supports UHRF2 as a bona fide 5hmC reader and further demonstrates a role for 5hmC in neuronal function.
Highlights
UHRF2 has been implicated as a novel regulator for both DNA methylation (5mC) and hydroxymethylation (5hmC), but its physiological function and role in DNA methylation/ hydroxymethylation are unknown
From our RNA-seq data, we found that the expression levels of Tet1, Tet2, and Tet3 were not affected by the loss of UHRF2 (Fig. 5D)
We have taken the gene ablation approach to investigate the physiological role of UHRF2, a novel protein that has been shown to bind three epigenetic markers (H3K9me2/3, 5mC, and 5hmC) and has been implicated in epigenetic and cell cycle regulation in mice
Summary
5mC, DNA methylation at the C5 position of cytosine; 5hmC, 5-hydroxymethylcytosine; US, unconditioned stimulus; CS, conditioned stimulus; H3K9, histone H3 Lys-9; ES cell, embryonic stem cell; IHC, immunohistochemistry; ANOVA, analysis of variance; RNA-seq, RNA sequencing; MEF, mouse embryo fibroblast; OGT, O-GlcNAc transferase; PFA, paraformaldehyde. Reduced 5hmC and Defective Learning and Memory homeodomain that bind cooperatively the H3 tails with H3K9me2/3, and a C-terminal RING finger domain that confers a ubiquitin E3 ligase activity (16 –18). Despite their sequence and biochemical similarity, we and others showed previously that UHRF2 cannot substitute for UHRF1 in supporting DNA maintenance methylation [16, 17]. Recent studies have begun to reveal a critical role for epigenetic modification of DNA, including 5mC and 5hmC, and TET1 enzyme in neurogenesis, learning, memory consolidation, and extinction (20 –24). We provide evidence that UHRF2 binds 5hmC in vivo but does not appear to affect TET1 enzymatic activity
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