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UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures [RNA-seq]

ABSTRACT: 5-methylcytosine (5mC) regulates multiple cellular processes and is faithfully maintained following DNA replication. Ubiquitin-like PHD and ring finger domain-containing protein 1 (UHRF1) plays an important role in the maintenance of 5mC levels. Interestingly, UHRF1 has a paralog UHRF2 that has similar sequence and domain architecture, but the biological function of UHRF2 is not clear. Here, we have generated Uhrf2 knockout mice and characterized the role of UHRF2 in vivo. Uhrf2 knockout mice are viable, but the adult mice develop frequent spontaneous seizures and display abnormal electrical activities in brain. To explore possible mechanism beyond these phenomenon, we utilized high-throughput sequencing to identify global expression changes in Uhrf2 knockout mice brains. In addition, we explored genome-wide 5mc profiles in these samples to examine if UHRF2 regulates 5mc levels in specific genome loci.

ORGANISM(S): Mus musculus

PROVIDER: GSE98360 | GEO | 2017/07/21

SECONDARY ACCESSION(S): PRJNA384843

REPOSITORIES: GEO

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UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures [MeDIP-Seq, hMeDIP-Seq]

Project description:5-methylcytosine (5mC) regulates multiple cellular processes and is faithfully maintained following DNA replication. Ubiquitin-like PHD and ring finger domain-containing protein 1 (UHRF1) plays an important role in the maintenance of 5mC levels. Interestingly, UHRF1 has a paralog UHRF2 that has similar sequence and domain architecture, but the biological function of UHRF2 is not clear. Here, we have generated Uhrf2 knockout mice and characterized the role of UHRF2 in vivo. Uhrf2 knockout mice are viable, but the adult mice develop frequent spontaneous seizures and display abnormal electrical activities in brain. To explore possible mechanism beyond these phenomenon, we utilized high-throughput sequencing to identify global expression changes in Uhrf2 knockout mice brains. In addition, we explored genome-wide 5mc profiles in these samples to examine if UHRF2 regulates 5mc levels in specific genome loci.

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UHRF2 Commissions the Accomplishment of DNA Demethylation through Allosteric Activation by 5hmC and K33-linked Ubiquitination of XRCC1

Project description:The transition of oxidized 5-methylcytosine (5mC) intermediates into base excision repair (BER) pipeline to complete DNA demethylation remains enigmatic. We report here that UHRF2, the only paralog of UHRF1 in mammals that is neither able to maintain 5mC nor to rescue Uhrf1-/- phenotype, is physically and functionally associated with BER. UHRF2 is allosterically activated by 5-hydroxymethylcytosine (5hmC) and acts as a ubiquitin E3 ligase to catalyze K33-linked polyubiquitination of XRCC1, a core subunit of the BER complex. This nonproteolytic action stimulates the interaction of XRCC1 with the ubiquitin binding domain-bearing RAD23B, leading to the formation of the TDG-RAD23B-BER complex amenable to complete DNA demethylation. Integrative epigenomic analysis in mouse embryonic stem cells reveals that the Uhrf2-coordinated TDG-RAD23B-BER complex functionally links to the completion of DNA demethylation at promoters, and that during neuronal commitment, Uhrf2-associated and H3K4me1-marked latent enhancers undergo poised-to-active transition accompanied by H3K27ac acquisition. Accordingly, Uhrf2 ablation impairs DNA demethylation and abolishes neuronal differentiation. Together, these observations highlight the essentiality of 5hmC-switched UHRF2 E3 ligase activity in commissioning the accomplishment of active DNA demethylation.

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UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures

Project description:UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures

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UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures.

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UHRF2 regulates local 5-methylcytosine and suppresses spontaneous seizures

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-07-21 | GSE98362 | GEO

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