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DUSP9 is a dose-dependent, X-linked modulator of female DNA hypomethylation in mouse pluripotent stem cells

ABSTRACT: Blastocyst-derived embryonic stem cells (ESCs) and gonad-derived embryonic germ cells (EGCs) represent two classic types of pluripotent cell lines, yet their molecular equivalence remains incompletely understood. Here, we compare genome-wide methylation patterns between isogenic ESC and EGC lines to define epigenetic similarities and differences. Surprisingly, we find that sex rather than cell type drives methylation patterns in ESCs and EGCs. Cell fusion experiments further reveal that the ratio of X-chromosomes to autosomes dictates methylation levels, with female hybrids being hypomethylated and male hybrids being hypermethylated. We show that the X-linked MAPK phosphatase DUSP9 is upregulated in female compared to male ESCs, and its heterozygous loss in female ESCs leads to male-like methylation levels. Notably, male and female blastocysts are similarly hypomethylated, indicating that sex-specific methylation differences arise in culture. Collectively, our data demonstrate the epigenetic similarity of sex-matched ESCs and EGCs and identify DUSP9 as a regulator of female-specific hypomethylation.

ORGANISM(S): Mus musculus

PROVIDER: GSE94481 | GEO | 2017/05/18

SECONDARY ACCESSION(S): PRJNA369837

REPOSITORIES: GEO

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DUSP9 Modulates DNA Hypomethylation in Female Mouse Pluripotent Stem Cells

Project description:Blastocyst-derived embryonic stem cells (ESCs) and gonad-derived embryonic germ cells (EGCs) represent two classic types of pluripotent cell lines, yet their molecular equivalence remains incompletely understood. Here, we compare genome-wide methylation patterns between isogenic ESC and EGC lines to define epigenetic similarities and differences. Surprisingly, we find that sex rather than cell type drives methylation patterns in ESCs and EGCs. Cell fusion experiments further reveal that the ratio of X chromosomes to autosomes dictates methylation levels, with female hybrids being hypomethylated and male hybrids being hypermethylated. We show that the X-linked MAPK phosphatase DUSP9 is upregulated in female compared to male ESCs, and its heterozygous loss in female ESCs leads to male-like methylation levels. However, male and female blastocysts are similarly hypomethylated, indicating that sex-specific methylation differences arise in culture. Collectively, our data demonstrate the epigenetic similarity of sex-matched ESCs and EGCs and identify DUSP9 as a regulator of female-specific hypomethylation.

2017-04-12 | GSE68733 | GEO

PGC reversion to pluripotency involves erasure of DNA methylation from imprinting control centers followed by locus-specific re-methylation

Project description:Primordial germ cells (PGCs) are fate restricted to differentiate into gametes in vivo. However when removed from their embryonic niche PGCs undergo reversion to generate pluripotent embryonic germ cells (EGCs) in vitro. One of the major differences between EGCs and embryonic stem cells (ESCs) involves variable methylation at imprinting control centers (ICCs), a phenomenon that is poorly understood. In the current study we show that reverting PGCs to EGCs involves ICC methylation erasure, which remain stably hypomethylated at Snrpn, Igf2r and Kcnqot1. In contrast, the H19/Igf2 ICC undergoes almost complete de novo remethylation. Using the same approach for PGCs differentiated in vitro from ESCs we show that the Snrpn ICC is erased however the hypomethylated state is highly unstable. We also discovered that when the H19/Igf2 ICC is abnormally hypermethylated in ESCs, ICC methylation is not erased with differentiation into PGCs. This highlights the importance of not only launching germline differentiation with correctly methylated ESC lines but also the need to better stabilize the hypomethylated state in the in vitro derivatives following ICC erasure.

2015-06-01 | GSE69354 | GEO

Naïve pluripotency is associated with global DNA hypomethylation

2013-02-17 | GSE43398 | GEO

Oxygen effect on murine progenitor oligodrendrocytes

Project description:Hyperoxia is known to cause cerebral white matter injury in preterm infants with male sex being identified as an independent risk factor for poor neurodevelopmental outcome. We investigated the underlying mechanisms behind such a sex dependent difference by a comaparative protein profiling of male and female murine progenitor oligodendrocytes treated with 3 % or 80% oxygen. We demonstrate that following hyperoxia, the male derived oligodendrocyte progenitor cells (OPCs) are severely affected with respect to their energy metabolism, stress response and especially, maturation as compared to their female counterparts.

2021-09-08 | PXD011348 | Pride

NaÃ¯ve pluripotency is associated with global DNA hypomethylation

Project description:Naive pluripotent embryonic stem cells (ESCs) and embryonic germ cells (EGCs) are derived from the preimplantation epiblast and primordial germ cells (PGCs), respectively. We investigated whether differences exist between ESCs and EGCs, in view of their distinct developmental origins. PGCs are programmed to undergo global DNA demethylation; however, we find that EGCs and ESCs exhibit equivalent global DNA methylation levels. Importantly, inhibition of Erk and Gsk3b by 2i conditions leads to pronounced reduction in DNA methylation in both cell types. This is driven by Prdm14 and is associated with downregulation of Dnmt3a and Dnmt3b. However, genomic imprints are maintained in 2i, and we report derivation of EGCs with intact genomic imprints. Collectively, our findings establish that culture in 2i instills a naive pluripotent state with a distinctive epigenetic configuration that parallels molecular features observed in both the preimplantation epiblast and nascent PGCs. EGC lines were derived from E8.5 mouse embryos using three different protocols: FCS+LIF on MEFs (FCS, n = 4)), FCS+LIF on MEFs for 48 hours followed by 2i+LIF (2is, n = 4), and direct derivation into 2i+LIF (2i, n = 4). ESC lines were derived in either FCS+LIF on MEFs or in 2i+LIF conditions and once established the cell lines were also switched between the two culture environments (n = 5 for each culture condition). All cell lines were derived from genetically identical embryos.

2013-02-17 | E-GEOD-43398 | biostudies-arrayexpress

Analysis of sex chromosomes effect on hybrid male sterility

Project description:Sex chromosomes and more particularely the X chromosomes are known to have a major effect on hybrid male sterility. In this experiment by making use of the reciprocal hybrids between D. simulans and D. sechellia, we are showing the effect of these chromosomes on gene expression in male hybrids Keywords: X chromosome, hybrid Testes from for days old individuals (D. simulans, D. sechellia, hybrid D. simulans female x D. sechellia male, hybrid D. sechellia female x D. simulans male) were dissected and RNA was extracted and hybridized along with a reference RNA from the whole body of 4 days old D. melanogaster male. Gene expression in hybrids were compared to parental gene expression in order to isolate misexpressed genes in each hybrids. In order to reveal the cross effect misexpressed genes in hybrids were compared to identify genes commonly misexpressed and genes genes misexpressed in only one hybrid.

2009-11-01 | E-GEOD-4677 | biostudies-arrayexpress

A partially sex-reversed giant kelp sheds light into the mechanisms of sexual differentiation in UV sexual system

Project description:In UV sexual systems, sex is determined during the haploid phase of the life cycle and males have a V chromosome whereas females have a U chromosome. Previous work in the model Ectocarpus revealed that the V chromosome has a dominant role in male sex determination and the female developmental program being a ‘default’ program, triggered in the absence of the male master sex determination gene(s). Here, we describe the identification of a genetically male giant kelp strain presenting phenotypic features typical of a female, despite lacking the U-specific region. The conversion to the female developmental program is however incomplete, because gametes of this feminised male are unable to produce the sperm-attracting pheromone lamoxiren. We identify the transcriptomic pathways underlying the male and female specific developmental programs and show that the phenotypic feminisation of the variant strain is associated with both feminisation and de-masculinisation of gene expression patterns. Importantly, the feminisation phenotype was associated with the dramatic downregulation of two V-specific genes including a candidate sex-determining gene on the V-specific region. Our results reveal the transcriptional changes associated with sexual differentiation in a UV system with extensive sexual dimorphism, disentangling the role of sex-linked genes and autosomal gene expression in the initiation of the male and female developmental programs. Overall, the data presented here imply that the U-specific region in the giant kelp is not required to initiate the female developmental program, but is critical to produce fully functional eggs, arguing against the idea that female is the ‘default’ sex in this species.

2022-04-28 | GSE165423 | GEO

Genome-wide DNA methylation map of Zebrafish male and female brain

Project description:Using 2 male and 2 female zebrafish (pool of 6) brain samples, we generated base-resolution DNA methylation maps to document sex-specific epigenetic differences.

2014-10-01 | GSE59916 | GEO

Sex-based comparison of CD4+ T cell DNA methylation patterns in SLE reveals pro-inflammatory epigenetic changes in men

Project description:Male patients with systemic lupus erythematosus (SLE) experience severe disease compared to female patients, despite the disease being more prevalent in females. For the time, we compared genome-wide differential methylation in CD4+ T cells between male (n=12) and female (n=10) SLE patients.

2023-06-07 | GSE207861 | GEO

Analysis of sex chromosomes effect on hybrid male sterility

2009-11-01 | GSE4677 | GEO

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