Original PKC inhibitors regulate stem cell self-renewal by regulating H3K27me3 and H3K9me3

Sun, Jialei1; He, Na2; Wang, Weiguo1; Dai, Yujian1; Hou, Chunhui3; Du, Fuliang1

2022

American Journal of Translational Research   Impact Factor & Quartile

1943-8141

Embryonic stem cell (ESC) research is critical to the scientific community, as their application in regenera-tive medicine can be widely beneficial. ESCs eventually withdraw from their self-renewal program and subsequent-ly differentiate into specific cell lineages; however, the mechanisms regulating these processes remain unclear. PKC inhibition using 3-[1-[3-(dimethylamino) propyl]-5-methoxy-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione (PKCi) is responsible for the derivation and maintenance of human, rat, and mouse ESCs, but the mechanism by which PKCi maintains stem cell self-renewal is poorly understood. By studying the PKCi stem cell (PKCi-mESC) transcriptome and epigenetic modification, we found the transcriptome of PKCi-mESC differed from 2i stem cells (2i-mESC), with 2010 up-regulated genes and 1784 down-regulated genes. Among them, genes related to core transcription factors, naive-specific markers, and pluripotency are differentially expressed between the two stem cell lines. We analyzed epigenetic modification of PKCi-mESC and found the distribution of H3K27me3 signal was significantly reduced at transcription start sites (TSSs) throughout the genome and at differentially expressed genes (DEGs). Likewise, the H3K9me3 signal at TSSs throughout the genome was significantly reduced in PKCi-mESC, but the distribution on DEGs is reversed. Kdm4d and Kdm6a knockdown by RNA interference (RNAi) significantly altered the expression of genes related to self-renewal in PKCi-mESC. In conclusion, we revealed PKCi-mESC and 2i-mESC differentially express numerous genes, including stem cell-related genes. Furthermore, PKCi-mESC regulated gene expression through H3K27me3 and H3K9me3 modification, which maintained stem cell self-renewal capacity.

Mouse mESC PKCi self-renewal histone modification

SCI

English

Corresponding

Natural Science Foundation of China (NSFC)["31872353","32072732","31340041","31471388"] ; National Key Ramp;D Program of China[2018YFC1004500] ; Stable Support Plan Program of Shenzhen Natural Science Fund[20200925153547003] ; Shenzhen Innovation Committee of Science and Technology[ZDSYS202008111440020-08] ; Southern University of Science and Technology["G02226301","Y01501821"]

Oncology ; Research & Experimental Medicine

Oncology ; Medicine, Research & Experimental

WOS:000891236800008

E-CENTURY PUBLISHING CORP

Web of Science

1.Nanjing Normal Univ, Coll Life Sci, Jiangsu Key Lab Mol & Med Biotechnol, 1 Wenyuan Rd, Nanjing 210046, Peoples R China
2.Harbin Inst Technol, Harbin 150001, Heilongjiang, Peoples R China
3.Southern Univ Sci & Technol, Sch Life Sci, Dept Biol, Shenzhen Key Lab Gene Regulat & Syst Biol, Shenzhen 518055, Guangdong, Peoples R China

Sun, Jialei,He, Na,Wang, Weiguo,et al. Original PKC inhibitors regulate stem cell self-renewal by regulating H3K27me3 and H3K9me3[J]. American Journal of Translational Research,2022,14(6).

Sun, Jialei,He, Na,Wang, Weiguo,Dai, Yujian,Hou, Chunhui,&Du, Fuliang.(2022).Original PKC inhibitors regulate stem cell self-renewal by regulating H3K27me3 and H3K9me3.American Journal of Translational Research,14(6).

Sun, Jialei,et al."Original PKC inhibitors regulate stem cell self-renewal by regulating H3K27me3 and H3K9me3".American Journal of Translational Research 14.6(2022).