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TET1-JMJD3-H3K27me3 targets and regulates Pramel3 to affect spermatogonia self-renewal and proliferation and differentiation

ABSTRACT: Histone modification and DNA methylation among epigenetic modifications play a coordinated role in the regulation of spermatogonia. Tet methylcytosine dioxygenase 1 (TET1) can either act as a DNA demethylase, converting 5-methylcytosine to 5-hydroxymethylcytosine or regulate gene expression by forming a complex with other proteins. Increased levels of H3K27me3 will result in transcriptional repression and reduced or silenced protein expression. However, the mechanism by which TET1 mediates the regulation of H3K27me3 in spermatogonia and the target genes that act is not clear. The results of this study showed that the expression of self-renewal-related gene GFRA1 and proliferation-related gene PCNA were up-regulated after JMJD3 overexpression. Moreover, it was demonstrated that TET1 and JMJD3 can interact with H3K27me3 by forming a protein complex, and the CHIP-Seq sequencing results analyzed that TET1 targets and regulates the Pramel3 gene when interacting with H3K27me3, and TET1 overexpression promotes the up-regulation of Pramel3 expression. Our study identified a novel link between TET1 and H3K27me3 and established a TET1-JMJD3-H3K27me3-Pramel3 regulatory axis to regulate spermatogonia self-renewal, proliferation and differentiation. It provides a new idea to further investigate the mechanism of spermatogenesis and spermatogenic disorders from the epigenetic level.

ORGANISM(S): Mus musculus

PROVIDER: GSE233150 | GEO | 2023/05/24

REPOSITORIES: GEO

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Project description:Epigenetic modification of the mammalian genome by DNA methylation (5-methylcytosine) has a profound impact on chromatin structure, gene expression and maintenance of cellular identity. Recent demonstration that members of the Ten-eleven translocation (Tet) family proteins can convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) raised the possibility that Tet proteins are capable of establishing a distinct epigenetic state. We have recently demonstrated that Tet1 is specifically expressed in murine embryonic stem (ES) cells and is required for ES cell self-renewal and maintenance. Using chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq), here we show that Tet1 is preferentially bound to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Despite a general increase in levels of DNA methylation at Tet1 binding-sites, Tet1 depletion does not lead to down-regulation of all the Tet1 targets. Interestingly, while Tet1-mediated promoter hypomethylation is required for maintaining the expression of a group of transcriptionally active genes, it is also required for repression of Polycomb-targeted developmental regulators. Tet1 contributes to silencing of this group of genes by facilitating recruitment of PRC2 to CpG-rich gene promoters. Thus, our study not only establishes a role for Tet1 in modulating DNA methylation levels at CpG-rich promoters, but also reveals a dual function of Tet1 in promoting transcription of pluripotency factors as well as participating in the repression of Polycomb-targeted developmental regulators. Mouse ES cells infected with control knockdown (KD) or Tet1 KD lentiviruses were FACS-sorted for RNA extraction and hybridization on Affymetrix microarrays. We also investigated the effect of Nanog overexpression (OE) in Tet1 KD mouse ES cells on dys-regulated Tet1 targets. We have collected four biologically independent replicates for each treatment.

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TET1-JMJD3-H3K27me3 targets and regulates Pramel3 to affect spermatogonia self-renewal and proliferation and differentiation

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