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Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate.

ABSTRACT: Rcor2, the corepressor 2 of REST, a transcriptional repressor, is predominantly expressed in embryonic stem cells (ESCs) and plays a major role in regulating ESC pluripotency and neurogenesis. The function of Rcor2 in development of other germ layers is yet unclear. We utilized a Rcor2^-/- mouse embryonic stem cell (mESC) line to investigate the role of Rcor2 in mESC differentiation. Rcor2^-/- mESC shows reduced proliferation and severely compromised capacity to differentiate to all three germ layers. In contrast, Rcor2 knockout promotes primordial germ cells (PGCs) specific gene expression and possibly PGC formation. Mechanistically, we revealed that Rcor2 inhibits expression of genes required for PGC development, such as Dppa3 and Dazl, by associating to their promoters and enhancing local suppressive H3K9me3 modifications. Our results suggest that Rcor2 plays an important role in somatic cell fate determination by suppressing PGC differentiation through regulating epigenetic modifications of PGC specific genes.

SUBMITTER: Pei L

PROVIDER: S-EPMC8957467 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate.

Pei Lijuan L Zhang Hongjie H Zhang Meihui M Wang Yixuan Y Wei Ke K

Stem cells international 20220319

Rcor2, the corepressor 2 of REST, a transcriptional repressor, is predominantly expressed in embryonic stem cells (ESCs) and plays a major role in regulating ESC pluripotency and neurogenesis. The function of Rcor2 in development of other germ layers is yet unclear. We utilized a Rcor2-/- mouse embryonic stem cell (mESC) line to investigate the role of Rcor2 in mESC differentiation. Rcor2-/- mESC shows reduced proliferation and severely compromised capacity to ...[more]

PMID: 35345626

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Project description:BackgroundCancer/testis-antigens (CTAs) are specifically expressed in human malignancies and testis tissue, but their molecular functions are poorly understood. CTAs serve as regulators of gene expression, cell cycle and spermatogenesis, as well as targets for immune-based therapies. The CTA PRAME is expressed in various cancers, antagonises retinoic acid signalling and is regulated by DNA methylation and histone acetylation.MethodsWe analysed the molecular function of the CTA PRAME in primordial germ cells (PGC) and testicular germ cell cancers (GCC). GCCs arise from a common precursor lesion termed germ cell neoplasia in situ (GCNIS), which itself is thought to originate from a defective PGC. GCNIS cells eventually develop into unipotent seminomas or totipotent embryonal carcinomas (ECs), which are capable of differentiation into teratomas, yolk-sac tumours and choriocarcinomas.ResultsPRAME is, like the master regulator of PGCs SOX17 expressed in human PGCs, GCNIS and seminomas but absent in ECs. shRNA-mediated knockdown of PRAME in seminomatous TCam-2 cells left SOX17 levels unchanged, but resulted in downregulation of pluripotency- and PGC-related genes (LIN28, PRDM14, ZSCAN10), whereas somatic and germ cell differentiation markers were upregulated. So, PRAME seems to act downstream of SOX17 by mediating the regulation of the germ cell differentiation and pluripotency programme. Endoderm differentiation is triggered in somatic cells by SOX17, suggesting that in PGCs, PRAME represses this programme and modulates SOX17 to function as a PGC-master regulator. Surprisingly, knockdown of PRAME in TCam-2 cells did not render the cells sensitive towards retinoic acid, despite the fact that PRAME has been described to antagonise retinoic acid signalling. Finally, we demonstrate that in non-seminomas PRAME expression is silenced by DNA methylation, which can be activated by formation of euchromatin via histone-deacetylase-inhibitors.ConclusionsWe identified the CTA PRAME as a downstream factor of SOX17 and LIN28 in regulating pluripotency and suppressing somatic/germ cell differentiation in PGC, GCNIS and seminomas.

Dataset Information

Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate.

Publications

Rcor2 Is Required for Somatic Differentiation and Represses Germline Cell Fate.

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