Polycomb group RING finger protein 5 influences several developmental signaling pathways during the in vitro differentiation of mouse embryonic stem cells

Abstract

Polycomb group (PcG) RING finger protein 5 (PCGF5) is a core component of the so‐called Polycomb repressive complex 1.5 (PRC1.5), which is involved in epigenetic transcriptional repression. To explore the developmental function of Pcgf5, we generated Pcgf5 knockout (Pcgf5−/−) mouse embryonic stem cell (mESC) lines with the help of CRISPR/Cas9 technology. We subjected the Pcgf5−/− and wild‐type (WT) mESCs to a differentiation protocol toward mesodermal‐cardiac cell types as aggregated embryoid bodies (EBs) and we found that knockout of Pcgf5 delayed the generation of the three germ layers, especially the ectoderm. Further, disruption of Pcgf5 impacted the epithelial‐mesenchymal transition during EB morphogenesis and differentially affected the gene expression of essential developmental signaling pathways such as Nodal and Wnt. Finally, we also unveiled that loss of Pcgf5 induced the repression of genes involved in the Notch pathway, which may explain the enhancement of cardiomyocyte maturation and the dampening of ectodermal‐neural differentiation observed in the Pcgf5−/− EBs.

Changes in chromatin accessibility landscape and histone H3 core acetylation during valproic acid-induced differentiation of embryonic stem cells

“…Importantly, in response to VPA, we also observed a significant increase in H3K56ac enrichment the TSS of Tnnt3 that overlapped with the observed ATAC-seq peak gain in the same genomic location, suggesting a coordinate transition toward a transcriptionally permissive chromatin environment. In addition, highly significant increases in chromatin accessibility at loci, such as alpha-T-catenin (Ctnn3) and polycomb group ring finger 5 (Pcgf5), further suggest that VPA exposure leads to changes in chromatin structure at specific key regulatory factors of cardiac and neuronal differentiation programs [ 43 , 44 ]. Intriguingly, loss of chromatin accessibility at putative downstream enhancer regions within the Hopx locus suggests that HOPX expression levels may be subjected to HDACi effects in mESCs.…”

Pcgf5: An important regulatory factor in early embryonic neural induction

“…Neurodevelopmental processes are regulated by multiple factors that interact with various signaling pathways, including Notch, Wnt, Hedgehog, and TGF-β/BMP signaling pathways [ 37 ]. Pcgf5 is also involved in the regulation of multiple signaling pathways, such as the Notch and Wnt pathways [ 38 ]. It has been found that the loss of the Pcgf5 gene inhibits the expression of Notch1, thereby suppressing neural ectoderm differentiation [ 38 ], which is consistent with our findings.…”

“…Pcgf5 is also involved in the regulation of multiple signaling pathways, such as the Notch and Wnt pathways [ 38 ]. It has been found that the loss of the Pcgf5 gene inhibits the expression of Notch1, thereby suppressing neural ectoderm differentiation [ 38 ], which is consistent with our findings. However, it is unclear whether there is an interaction and co-regulation between the Notch and Wnt signaling pathways in the process of neural development.…”

Comparative analysis of the DNA methylation landscape in CD4, CD8, and B memory lineages

“…Several lincRNA-related loci were found to have altered methylation during memory activation in all three lineages, including LINC01258 locus to be demethylated in the memory lineages. LINC01258 is an ncRNA that targets the PCGF5 polycomb complex, which has a key role in differentiation and the NOTCH signaling pathway [ 56 ]. LINC01258 is upregulated in type 1 diabetes, a well-known immune disease [ 57 ].…”