Control of epigenomic landscape and development of fetal male germ cells through L-serine metabolism
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ABSTRACT:
PROVIDER: PRJNA1097648 | ENA |
REPOSITORIES: ENA
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Project description:Sex-specific metabolic characteristics emerge in the mouse germline after reaching the genital ridges around embryonic day 10.5, coinciding with the initiation of sexual differentiation. However, the impact of such metabolic characteristics on the development of male and female germ cells remains unclear. In this study, we observed the specific upregulation in male fetal germ cells of D-3-phosphoglycerate dehydrogenase (PHGDH), the primary enzyme in the serine-glycine–one-carbon (SGOC) metabolic pathway. A concurrent increase was observed in a downstream metabolite, S-adenosylmethionine (SAM), a crucial substrate for protein and nucleic acid methylation. Inhibiting PHGDH in fetal testes resulted in reduced SAM levels in germ cells, accompanied by increases in the number of germ cells and the undifferentiated spermatogonia ratio. Furthermore, PHGDH inhibition led to a decrease in the methylation of histone H3 and DNA, resulting in aberrations in gene expression profiles. In summary, our findings underscore the significant role of certain metabolic mechanisms in the development of male germ cells.
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Project description:Organoids derived from human pluripotent stem cells recapitulate the early three-dimensional organization of human brain, but whether they establish the epigenomic and transcriptional programs essential for brain development is unknown. We compared epigenomic and gene regulatory features in cerebral organoids and human fetal brain, using genome-wide, base resolution DNA methylome and transcriptome sequencing. Transcriptomic dynamics in organoids faithfully modeled gene expression trajectories in early-to-mid human fetal brains. We found that early non-CG methylation accumulation at super-enhancers in both fetal brain and organoids marks forthcoming transcriptional repression in the fully developed brain. 74% of 35,627 demethylated regions identified during organoid differentiation overlapped with fetal brain regulatory elements. Interestingly, pericentromeric repeats showed widespread demethylation in multiple types of in vitro human neural differentiation models but not in fetal brain. Our study reveals that organoids recapitulate many epigenomic features of mid-fetal human brain and also identified novel non-CG methylation signatures of brain development.
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Project description:The proper development of fetal germ cells (FGCs) is vital for genetic and epigenetic information transmission in generations. We have depicted the transcriptional landscape of distinct phases FGCs and the interaction between FGCs and gonadal niche cells. However, the epigenetic dynamics of sequential phases FGCs still remains in dimness. Here applied with single cell sequencing techniques (scBS-seq and scCOO-seq), we analyzed the genome-wide DNA methylation and chromatin accessibility map of female mitosis, meiotic prophase, and oogenesis FGCs, as well as male mitosis and mitotic-arrest FGCs.
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Project description:The limited number of in vivo germ cells poses an impediment to genome-wide studies. Here, we applied a small-scale ChIP-Seq method on purified mouse fetal germ cells to generate genome-wide maps of four histone modifications (H3K4me3, H3K27me3, H3K27ac and H2BK20ac), facilitating the identification of active and repressed cis-regulatory elements in germ cells in vivo. Comparison of active chromatin state between somatic, embryonic stem cells (ESC) and germ cells revealed promoters and enhancers needed for stem cell maintenance and germ cell development. The nuclear receptor Nr5a2 motif is enriched at a subset of cis-regulatory regions and we confirm its role in germ cell differentiation. Interestingly, germ cells have comparatively more H3K27me3-marked sites that are absent in ESC and other somatic cell types. These repressed regions are enriched for retrotransposons and MHC genes and this indicates that these loci are specifically silenced in germ cells. Together, our study provides the first genome-wide histone modification maps of in vivo germ cells and revealed the molecular chromatin signatures unique to germ cells. Germ cells were FACS-purified from gonadal single cell suspension based on Pou5f1-GFP expression. ChIP-seq of Histone modification was done for two timepoints in this study: E11.5 (male/female), E13.5 (male). For E13.5 timepoint, two biological replicates were analyzed. In order to validate small scale ChIP-seq method limited number of ES cells were used to check consistency of ChIP-seq data.
2013-01-25 | E-GEOD-38164 | biostudies-arrayexpress
Project description:To better understand the underlying dynamics driving formation of the spermatogonial stem cell (SSC) pool during development, we performed single-cell RNA-sequencing on mouse germ cells isolated from testes during late fetal and early postnatal development. Transcriptome profiling revealed that a subset of prospermatogonia during late fetal development becomes preprogrammed to adopt the SSC fate in postnatal life. Further computational analysis mapped the transcriptional dynamics of the SSC trajectory through developmental time to identify novel pathways and regulators involved in formation of the foundational SSC pool. Paired with in vivo gene expression analysis via a multi-transgenic mouse model and functional assessment of germ cell fate via transplantation, the findings of our study present a model for which stem cell fate is preprogrammed in the spermatogenic lineage.
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Project description:The limited number of in vivo germ cells poses an impediment to genome-wide studies. Here, we applied a small-scale ChIP-Seq method on purified mouse fetal germ cells to generate genome-wide maps of four histone modifications (H3K4me3, H3K27me3, H3K27ac and H2BK20ac), facilitating the identification of active and repressed cis-regulatory elements in germ cells in vivo. Comparison of active chromatin state between somatic, embryonic stem cells (ESC) and germ cells revealed promoters and enhancers needed for stem cell maintenance and germ cell development. The nuclear receptor Nr5a2 motif is enriched at a subset of cis-regulatory regions and we confirm its role in germ cell differentiation. Interestingly, germ cells have comparatively more H3K27me3-marked sites that are absent in ESC and other somatic cell types. These repressed regions are enriched for retrotransposons and MHC genes and this indicates that these loci are specifically silenced in germ cells. Together, our study provides the first genome-wide histone modification maps of in vivo germ cells and revealed the molecular chromatin signatures unique to germ cells.
2013-01-25 | GSE38164 | GEO
Project description:Serine is a substrate for nucleotides, NADPH and glutathione (GSH) synthesis. Previous studies in cancer cells and lymphocytes have shown that serine-dependent one-carbon units are necessary for nucleotide production to support proliferation. Presently, it is unknown whether serine metabolism impacts the function of non-proliferative cells, such as inflammatory macrophages. We find that in macrophages, serine is required for optimal lipopolysaccharide (LPS) induction of IL-1β mRNA expression, but not inflammasome activation. The mechanism involves a requirement for glycine, which is made from serine, to support macrophage glutathione (GSH) synthesis. Cell-permeable GSH, but not the one-carbon donor formate, rescues IL-1β mRNA expression. Pharmacological inhibition of de novo serine synthesis in vivo decreased LPS induction of IL-1β levels and improved survival in an LPS-driven model of sepsis in mice. Our study reveals that serine metabolism is necessary for GSH synthesis to support IL-1β cytokine production.
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