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SWI/SNF chromatin remodeling complex is required for initiation of sex-dependent differentiation in mouse germline

ABSTRACT: Sexual reproduction involves the creation of sex-dependent gametes, oocytes and sperm. In mammals, sexually dimorphic differentiation commences in the primordial germ cells (PGCs) in embryonic gonads; PGCs in ovaries and testes differentiate into meiotic primary oocytes and mitotically quiescent prospermatogonia, respectively. Here, we show that the transition from PGCs to　sex-specific germ cells was abrogated in conditional knockout mice carrying a null mutation of Smarcb1 (also known as Snf5) gene, which encodes a core subunit of the SWI/SNF chromatin remodeling complex. In female mutant mice, failure to upregulate meiosis-related genes resulted in impaired meiotic entry and progression, including defects in synapsis formation and DNA repair. Mutant male mice exhibited delayed mitotic arrest and DNA hypomethylation in retrotransposons and imprinted genes, resulting from aberrant expression of genes related to growth and de novo DNA methylation. Collectively, our results demonstrate that the SWI/SNF complex is required for transcriptional reprogramming in the initiation of sex-dependent differentiation of germ cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE154209 | GEO | 2021/12/15

REPOSITORIES: GEO

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SWI/SNF chromatin remodeling complex coordinates the meiotic gene activation via promoter remodeling and Meiosin activation in female germline

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2022-11-17 | GSE203588 | GEO

Loss of Snf5 and the formation of an aberrant SWI/SNF complex

Project description:Aberrant forms of the SWI/SNF chromatin remodeling complex are associated with human disease. Loss of the Snf5 subunit of SWI/SNF is a driver mutation in pediatric rhabdoid cancers and forms aberrant sub-complexes that are not well characterized. We determined the effects of loss of Snf5 on the composition, nucleosome binding, recruitment and remodeling activities of yeast SWI/SNF. The Snf5 subunit interacts with the ATPase domain of Snf2 and forms a submodule consisting of Snf5, Swp82 and Taf14 as shown by mapping SWI/SNF subunit interactions by crosslinking-mass spectrometry and subunit deletion followed by immunoaffinity chromatography. Snf5 promoted binding of the Snf2 ATPase domain to nucleosomal DNA, enhanced its catalytic activity and facilitated nucleosome remodeling. Snf5 was required for acidic transcription factors to recruit SWI/SNF to chromatin. RNA-seq analysis suggested that both the recruitment and catalytic functions mediated by Snf5 are required for SWI/SNF regulation of gene expression.

2017-01-30 | GSE85460 | GEO

Bone Morphogenetic Protein and Retinoic Acid Synergistically Specify Female Germ Cell Fate in Mice

Project description:The mechanism for sex determination in mammalian germ cells remains unclear. Here, we reconstitute the female sex determination in mouse germ cells in vitro under a defined condition without the use of gonadal somatic cells. We show that retinoic acid (RA) and its key effector, STRA8, are not sufficient to induce the female germ-cell fate. In contrast, bone morphogenetic protein (BMP) and RA synergistically induce primordial germ cells (PGCs)/PGC-like cells (PGCLCs) derived from embryonic stem cells (ESCs) into fetal primary oocytes. The induction is characterized by the entry into the meiotic prophase, occurs synchronously and recapitulates cytological and transcriptome progression in vivo faithfully. Importantly, the female germ-cell induction necessitates a proper cellular competence–most typically, DNA demethylation of relevant genes–which is observed in appropriately propagated PGCs/PGCLCs, but not in PGCs/PGCLCs immediately after induction. This provides an explanation for the differential function of BMP signaling between PGC specification and female germ-cell induction. Ou findings represent a framework for a comprehensive delineation of the sex-determination pathway in mammalian germ cells, including humans.

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Multiple interactions of the oncoprotein transcription factor MYC with the SWI/SNF chromatin remodeler

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2020-12-15 | GSE153193 | GEO

DNA Damage Responses in Mouse Primordial Germ Cells [ncRNA-Seq]

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Project description:Primordial germ cells (PGCs) are precursors of both male and female gametes as fundamental materials for organism development. The transcriptome, methylome and chromatin accessibility profiles of PGCs in both mice and humans have been recently reported. However, little is known about the characteristics of PGCs at the protein levels, which directly exert cellular functions. Here, we construct landscapes of both proteome of mouse PGCs at E11.5, E13.5 and E16.5 days, the three critical developmental windows for PGCs’ sex differentiation, female meiosis initiation and male mitotic arrest. In each developmental stage of PGCs nearly 2000-3000 proteins are identified, among which specific functional pathways such as oxidative phosphorylation, DNA damage repair, and meiotic cell cycle are involved for different events during PGCs development. Thus, our work offers a valuable resource for the systematic investigations of PGC development at protein level.

2020-05-18 | PXD019222 | iProX

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2021-11-03 | PXD022452 | Pride

PRC1 coordinates timing of sexual differentiation of female primordial germ cells (RNA-Seq)

Project description:In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment1. In female PGCs, expression of Stimulated by retinoic acid 8 (Stra8) and meiosis are induced in response to retinoic acid (RA) provided by the mesonephroi2-4. Given the widespread role of RA signaling during development8,9, the molecular mechanism specifying the competence of PGCs to timely express Stra8 and enter meiosis are unknown2,10. Here we identify gene dosage dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb Repressive Complex 1 (PRC1)11,13. Both paralogs are essential for PGC development between day 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs for maintaining high levels of Oct4 and Nanog expression6, and for preventing premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of RA signaling partially suppresses precocious Oct4 down-regulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic RA signaling. Gene expression of mouse primordial germ cells was analysed using RNAseq method. Primodial germ cells were purified from embryos carrying Oct4(-delta-PE)-GFP transgene by FACS.

2013-03-14 | E-GEOD-42852 | biostudies-arrayexpress

PRC1 coordinates timing of sexual differentiation of female primordial germ cells

Project description:In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment1. In female PGCs, expression of Stimulated by retinoic acid 8 (Stra8) and meiosis are induced in response to retinoic acid (RA) provided by the mesonephroi2-4. Given the widespread role of RA signaling during development8,9, the molecular mechanism specifying the competence of PGCs to timely express Stra8 and enter meiosis are unknown2,10. Here we identify gene dosage dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb Repressive Complex 1 (PRC1)11,13. Both paralogs are essential for PGC development between day 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs for maintaining high levels of Oct4 and Nanog expression6, and for preventing premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of RA signaling partially suppresses precocious Oct4 down-regulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic RA signaling. Gene expression of mouse primordial germ cells was analysed using Affymetrix microarray. Primodial germ cells were purified from embryos carrying Oct4(deltaPE)-GFP transgene by FACS.

2013-03-14 | E-GEOD-42782 | biostudies-arrayexpress

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