1. The polycomb group protein PCGF6 mediates germline gene silencing by recruiting histone-modifying proteins to target gene promoters
- Author
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Fei Xing, Shuang Liu, Yin Xia, Qing Jiang, Jinzhong Qin, Mengjie Liu, and Yaru Zhu
- Subjects
0301 basic medicine ,Histone Deacetylase 2 ,Histone Deacetylase 1 ,Biology ,Biochemistry ,Cell Line ,Histones ,Mice ,03 medical and health sciences ,Histone methylation ,Animals ,Gene silencing ,Gene Silencing ,RNA-Seq ,Epigenetics ,Molecular Biology ,Mice, Knockout ,Polycomb Repressive Complex 1 ,Regulation of gene expression ,030102 biochemistry & molecular biology ,Mouse Embryonic Stem Cells ,Promoter ,Histone-Lysine N-Methyltransferase ,Cell Biology ,HDAC1 ,Cell biology ,030104 developmental biology ,Histone ,Histone methyltransferase ,biology.protein - Abstract
Polycomb group (PcG) proteins are essential for maintenance of lineage fidelity by coordinating developmental gene expression programs. Polycomb group ring finger 6 (PCGF6) has been previously reported to repress expression of lineage-specific genes, especially germ cell–related genes in mouse embryonic stem cells (ESCs) via the noncanonical polycomb repressive complex PRC1.6. However, the molecular mechanism of this repression remains largely unknown. Here, using RNA-Seq, real-time RT-PCR, immunohistochemistry, immunoprecipitation, and ChIP analyses, we demonstrate that PCGF6 plays an essential role in embryonic development, indicated by the partially penetrant embryonic lethality in homozygous PCGF6 (Pcgf6(−/−))-deficient mice. We also found that surviving Pcgf6-deficient mice exhibit reduced fertility. Using the Pcgf6-deficient mice, we observed that ablation of Pcgf6 in somatic tissues robustly derepresses germ cell–related genes. We further provide evidence that these genes are direct targets of PCGF6 in ESCs and that endogenous PCGF6 co-localizes with the histone-modifying proteins G9A histone methyltransferase (G9A)/G9a-like protein (GLP) and histone deacetylase 1/2 (HDAC1/2) on the promoters of the germ cell–related genes. Moreover, the binding of these proteins to their target genes correlated with methylation of Lys-9 of histone 3 and with the status of histone acetylation at these genes. Moreover, the recruitment of G9A/GLP and HDAC1/2 to target promoters depended on the binding of PCGF6. Our findings indicate that PCGF6 has a critical role in safeguarding lineage decisions and in preventing aberrant expression of germ cell–related genes.
- Published
- 2020