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Expression analysis suggests that DNMT3L is required for oocyte de novo DNA methylation only in Muridae and Cricetidae rodents

ABSTRACT: During early mammalian development, DNA methylation undergoes two waves of reprogramming, enabling transitions between somatic cells, oocyte and embryo. The first wave of de novo DNA methylation establishment occurs in the oocytes. Its molecular mechanisms has been studied in mouse, a classical mammalian model. Current dogma describes DNA methyltransferase 3A (DNMT3A) and its cofactor DNMT3L as two essential factors for oocyte DNA methylation – the ablation of either leads to nearly complete abrogation of DNA methylation. However, DNMT3L is not expressed in human oocytes, suggesting that the mechanism uncovered in mouse is not universal across mammals. We analyzed available RNA-seq datasets from oocytes of multiple mammals including our novel naked mole-rat oocytes dataset, and revealed that Dnmt3l is expressed only in the oocytes of mouse, rat and golden hamster. We identified a specific promoter sequence recognised by an oocyte transcription factor complex associated with Dnmt3l activity and demonstrated that it emerged in the rodent clade Eumuroida, comprising the families Muridae (mice, rats, gerbils) and Cricetidae (hamsters). Therefore, Dnmt3l is expressed and consequently plays a role in de novo DNA methylation only in the oocytes of these species, instead of being an essential pan-mammalian factor.

ORGANISM(S): Cavia porcellus Spalacopus cyanus Heterocephalus glaber

PROVIDER: GSE236457 | GEO | 2023/11/13

REPOSITORIES: GEO

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NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing

Project description:While de novo DNA methylation (DNAme) in mammalian germ cells is dependent upon DNMT3A and DNMT3L, oocytes and spermatozoa show distinct patterns of DNAme. In mouse oocytes, de novo DNAme requires the lysine methyltransferase (KMTase) SETD2, which deposits H3K36me3. Surprisingly, we show here that SETD2 is dispensable for de novo DNAme in the male germline. Rather, the KMTase NSD1, which broadly deposits H3K36me2 in euchromatic regions, plays a critical role in de novo DNAme in prospermatogonia, including of imprinted genes. However, males deficient in germline NSD1 show a more severe defect in spermatogenesis than Dnmt3l-/- males. Furthermore, unlike DNMT3L, NSD1 safeguards a subset of genes against H3K27me3-associated transcriptional silencing. In contrast, H3K36me2 plays only a minor role in de novo DNAme during oogenesis and females with NSD1 deficient oocytes are fertile. Thus, the sexually dimorphic pattern of DNAme in mature mouse gametes is driven by distinct profiles of H3K36 methylation.

2020-07-10 | GSE148150 | GEO

Dynamic Changes in Histone Modifications Precede de novo DNA Methylation in Oocytes

Project description:Erasure and subsequent re-instatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in non-dividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation and genome-wide sequencing (ChIP-Seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4me2 and H3K4me3 in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylases KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-Seq in oocytes, and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

2015-12-02 | GSE74549 | GEO

DNA methylation dynamics of oocyte in follicular maturation (RNA-Seq data set)

Project description:Folliculogenesis in mammals is a cyclic and hierarchical process that the ovarian follicles undergo dramatic changes in the shape and number of granulosa cells accompanied by gradually enlarged immature oocyte. Here we show a thorough and high-resolution view of DNA methylation maps in oocyte free of somatic cells present at each distinct follicular development stages. We found that global DNA establishment occurs in Type5b follicles, the final stage of pre-antral follicles, and that the acquisition of DNA methylation at different trans-regulatory elements couples with different chromatin modifiers. Besides, we showed that Dnmt1 as well as Uhrf1 also play critical roles in requiring and retaining of de novo methylation statue, typically at LINE and LTR elements, in these immature oocytes, which successfully escape DNA replication. Our study thus refined the current knowledge on the establishment of unique DNA methylation profile in mammalian oocytes, and provide a valuable resource for further studies on female gametogenesis.

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DNA methylation dynamics of oocyte in follicular maturation (ChIP-Seq data set)

2020-12-25 | GSE111686 | GEO

DNA methylation dynamics of oocyte in follicular maturation (RRBS-Seq data set)

2021-06-30 | GSE111684 | GEO

Identification of maternal imprinting control regions (ICRs) in the post-implantation mouse embryo.

2012-10-04 | GSE32687 | GEO

SPOCD1 is a novel executor of piRNA-directed DNA methylation that links MIWI2 to the de novo DNA methylation machiner

Project description:In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge, the necessity to erase and reset genomic methylation. In the male germline RNA-directed DNA methylation silences young active transposable elements (TEs). The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs (piRNAs) are proposed to tether MIWI2 to nascent TE transcripts and instruct DNA methylation. The mechanism by which MIWI2 directs de novo TE methylation is poorly understood but central to the immortality of the germline. Here, we define the interactome of MIWI2 in foetal gonocytes that are undergoing de novo genome methylation and identify a novel MIWI2-associated factor, SPOCD1, that is essential for young TE methylation and silencing. The loss of Spocd1 in mice results in male specific infertility and does not impact on piRNA biogenesis nor localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein and its expression is restricted to the period of de novo genome methylation. We found SPOCD1 co-purified in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery as well as constituents of the NURD and BAF chromatin remodelling complexes. We propose a model whereby tethering of MIWI2 to a nascent TE transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through its association with SPOCD1. In summary, we have identified a novel and essential executor of mammalian piRNA-directed DNA methylation.

2020-06-22 | PXD016701 | Pride

Identification of maternal imprinting control regions (ICRs) in the post-implantation mouse embryo.

Project description:Genomewide DNA methylation profiles, generated by MeDIP-seq, for 8.5dpc wildtype and Dnmt3l-/+ mouse embryos were compared to identify differentially methylated regions (DMRs) that depend on the activity of the de novo DNA methyltransferase cofactor Dnmt3l in the oocyte. These DMRs were further characterised by their methylation state in mature mouse sperm and in the livers of inter-subspecies newborn mice. Maternal ICRs were identified by hypomethylation in Dnmt3l-/+ embryos as well as sperm, and maternal allele-specific methylation in liver. MeDIP-seq for two pools of wildtype and two pools of Dnmt3l-/+ mouse 8.5dpc embryos, the sperm of three sires, and 12 pools of three different embryonic livers each. Sliding window read count comparison between wildtype and Dnmt3l-/+ embryos, and between wildtype embryos and sperm samples. Read count comparison between the parental alleles at known SNP sites in inter-subspecies liver data.

2012-10-04 | E-GEOD-32687 | biostudies-arrayexpress

PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

Project description:The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

| EGAS00001002903 | EGA

Dnmt3L-dependent regulation of DNA methylation promotes stem cells differentiation toward primitive germinal cells [MeDIP-seq]

Project description:The de novo DNA methyltransferase 3-like (Dnmt3L) is a catalytically inactive DNA methylase that has been previously shown to cooperate with Dnmt3a and Dnmt3b to methylate DNA. Dnmt3L is highly expressed in mouse embryonic stem cells (ESC) but its function in these cells is unknown. We here report that Dnmt3L is required for the differentiation of ESC into primordial germ cells (PGC) through activation of the homeotic gene Rhox5. By genome-wide analysis we found that Dnmt3L is a positive regulator of methylation at gene bodies of housekeeping genes and a negative regulator of methylation at promoters of bivalent genes. We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyl transferases Dnmt3a and Dnmt3b to maintain low the methylation level at H3H27me3 regions. Thus in ESC, Dnmt3L counteracts the activity of de novo DNA methylases to keep low the level of DNA methylation at developmental gene promoters. Examination of 5mC in shGFP and shDnmt3L ESC by MeDIP-Seq

2013-09-27 | E-GEOD-44642 | biostudies-arrayexpress

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