Dataset Information

Genome-wide maps of chromatin state in LbetaT2 cells or in the pituitary tissues of wild-type and Foxk2 knockout mice.

ABSTRACT: First, we report a series of ChIP-seq results in LbetaT2 cells. Briefly, we performed ChIP-seq experiments with antibodies specific for Foxk2, Sin3a, Tet1 and Uhrf1 in LbetaT2 cells. We found that a total of 343 different promoters including Nab2 that are co-targeted by Foxk2, Sin3a, Tet1 and Uhrf1. Next, hMeDIP-seq and ChIP-seq experiments with antibodies specific for 5hmC and H3K18ub in the pituitary tissues of wild-type and Foxk2 knockout mice were performed. The results showed that compared to the wild-type mice, knockout of Foxk2 reduced the enrichment of 5hmC and H3K18ub on the Foxk2 target gene.This study revealed a critical switch control of FOXK2 for GnRH pulse frequency-dependent LH production and gave us a new understanding of the role of Foxk2 in chromatin status and gene transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE130615 | GEO | 2020/05/01

REPOSITORIES: GEO

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Project description:Enzymatic erasure of DNA methylation in mammals involves iterative 5-methylcytosine (5mC) oxidation by the ten-eleven translocation (TET) family of DNA dioxygenase proteins. As the most abundant form of oxidized 5mC, the prevailing model considers 5-hydroxymethylcytosine (5hmC) as a key nexus in active DNA demethylation that can either indirectly facilitate replication-dependent depletion of 5mC by inhibiting maintenance DNA methylation machinery (UHRF1/DNMT1), or directly be iteratively oxidized to 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) and restored to cytosine (C) through thymine DNA glycosylase (TDG)-mediated 5fC/5caC excision repair. In proliferative somatic cells, to what extent TET-dependent removal of 5mC entails indirect DNA demethylation via 5hmC-induced replication-dependent dilution or direct iterative conversion of 5hmC to 5fC/5caC is unclear. Here we leverage a catalytic processivity stalling variant of human TET1 (TET1.var: T1662E) to decouple the stepwise generation of 5hmC from subsequent 5fC/5caC generation, excision and repair. By using a CRISPR/dCas9-based epigenome-editing platform, we demonstrate that 5fC/5caC excision repair (by wild-type TET1, TET1.wt), but not 5hmC generation alone (by TET1.var), is requisite for robust restoration of unmodified cytosines and reversal of somatic silencing of the methylation-sensitive, germline-specific RHOXF2B gene promoter. Furthermore, integrated whole-genome multi-modal epigenetic sequencing reveals that hemi-hydroxymethylated CpG dyads predominantly resist replication-dependent depletion of 5mC on the opposing strand in TET1.var-expressing cells. Notably, TET1.var-mediated 5hmC generation is sufficient to induce similar levels of differential gene expression (compared to TET1.wt) without inducing major changes in unmodified cytosine profiles across the genome. Our study suggests 5hmC alone plays a limited role in driving replication-dependent DNA demethylation in the presence of functional DNMT1/UHRF1 mechanisms, but can regulate gene expression as a bona fide epigenetic mark in proliferative somatic cells.

Dataset Information

Genome-wide maps of chromatin state in LbetaT2 cells or in the pituitary tissues of wild-type and Foxk2 knockout mice.

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