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The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE234968 | GEO | 2025/03/27

REPOSITORIES: GEO

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The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [WGBS]

Project description:DNA methylation (DNAme) controls gene expression, genome stability and cell identity in many mammalian organisms. Genomes of most somatic cells and spermatozoa are largely methylated, apart from CpG-dense sequences including gene promoters1. In mouse oocytes, DNAme is mostly limited to transcribed regions2,3. The mechanisms restricting global DNAme acquisition in developing oocytes and the relevance thereof for regulating gene expression and embryo development after fertilization are unknown. Here we show that the histone H3 lysine 36 dimethyl (H3K36me2) demethylases KDM2A and KDM2B redundantly execute multiple chromatin functions during oocyte development, which are vital to pre- and post-implantation development. Firstly, by serving as recruitment factors of variant Polycomb Repressive Complex 1 (vPRC1), they control genome-wide H2A mono-ubiquitination deposition (H2AK119u1) and PRC1-dependent gene repression4. Secondly, as demethylases, KDM2A/KDM2B prevent global H3K36me2 accumulation, thereby impeding DNMT3A-catalyzed de novo DNAme within PRC1-controlled promoter, genic, and intergenic regions, and even at non-PRC1-controlled CpG-dense gene promoters5. Decisively, we demonstrate that aberrant Dnmt3a-dependent DNAme established in Kdm2a/Kdm2b double mutant oocytes represses transcription from maternal loci in two-cell embryos and impairs pre-implantation development. Hence, KDM2A/KDM2B are essential for defining the appropriate oocyte DNA methylome which in turn conveys competence for early embryonic development. Our research implies that the reprogramming capacity eminent to early embryos is insufficient to erase aberrant DNAme from maternal chromatin. Lastly, our work shows that early development is vulnerable to gene dosage haplo-insufficiency effects, possibly in a parental-specific manner.

2025-03-27 | GSE234966 | GEO

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [RNA-seq]

2025-03-27 | GSE234965 | GEO

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [Cut&Run]

2025-03-27 | GSE234967 | GEO

Alternative isoforms of KDM2A and KDM2B lysine demethylases negatively regulate canonical Wnt signaling.

Project description:A precisely balanced activity of canonical Wnt signaling is essential for a number of biological processes and its perturbation leads to developmental defects or diseases. Here, we demonstrate that alternative isoforms of the KDM2A and KDM2B lysine demethylases have the ability to negatively regulate canonical Wnt signaling. These KDM2A and KDM2B isoforms (KDM2A-SF and KDM2B-SF) lack the N-terminal demethylase domain, but they still have the ability to bind to CpG islands in promoters and to interact with their protein partners via their other functional domains. We have observed that KDM2A-SF and KDM2B-SF bind to the promoters of axin 2 and cyclin D1, two canonical Wnt signaling target genes, and repress their activity. Moreover, KDM2A-SF and KDM2B-SF are both able to strongly repress a Wnt-responsive luciferase reporter. The transcriptional repression mediated by KDM2A-SF and KDM2B-SF, but also by KDM2A-LF, is dependent on their DNA binding domain, while the N-terminal demethylase domain is dispensable for this process. Surprisingly, KDM2B-LF is unable to repress both the endogenous promoters and the luciferase reporter. Finally, we show that both KDM2A-SF and KDM2B-SF are able to interact with TCF7L1, one of the transcriptional mediators of canonical Wnt signaling. KDM2A-SF and KDM2B-SF are thus likely to negatively affect the transcription of canonical Wnt signaling target genes by binding to their promoters and by interacting with TCF7L1 and other co-repressors.

| S-EPMC7588095 | biostudies-literature

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development

Project description:The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development

| PRJNA983810 | ENA

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [WGBS]

Project description:The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [WGBS]

| PRJNA983818 | ENA

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [RNA-seq]

Project description:The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [RNA-seq]

| PRJNA983814 | ENA

The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [Cut&Run]

Project description:The histone H3 lysine 36 demethylases KDM2A and KDM2B restrict DNMT3A-mediated de novo DNA methylation in oocytes to support embryonic development [Cut&Run]

| PRJNA983817 | ENA

KDM2A/B lysine demethylases and their alternative isoforms in development and disease.

Project description:Aberrant levels of histone modifications lead to chromatin malfunctioning and consequently to various developmental defects and human diseases. Therefore, the proteins bearing the ability to modify histones have been extensively studied and the molecular mechanisms of their action are now fairly well understood. However, little attention has been paid to naturally occurring alternative isoforms of chromatin modifying proteins and to their biological roles. In this review, we focus on mammalian KDM2A and KDM2B, the only two lysine demethylases whose genes have been described to produce also an alternative isoform lacking the N-terminal demethylase domain. These short KDM2A/B-SF isoforms arise through alternative promoter usage and seem to play important roles in development and disease. We hypothesise about the biological significance of these alternative isoforms, which might represent a more common evolutionarily conserved regulatory mechanism.

| S-EPMC7000146 | biostudies-literature

CpG islands recruit a histone H3 lysine 36 demethylase.

Project description:In higher eukaryotes, up to 70% of genes have high levels of nonmethylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over 20 years ago, but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, except that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36-specific lysine demethylase enzyme KDM2A. Nucleation of KDM2A at these elements results in removal of H3K36 methylation, creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that preferentially recognizes nonmethylated CpG DNA, and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.

| S-EPMC3098377 | biostudies-literature

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