TRIM28 and Interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes

Oleksiewicz, Urszula; Gładych, Marta; Raman, Ayush T.; Heyn, Holger; Mereu, Elisabetta; Chlebanowska, Paula; Andrzejewska, Anastazja; Sozańska, Barbara; Samant, Neha; Fąk, Katarzyna; Auguścik, Paulina; Kosiński, Marcin; Wróblewska, Joanna P.; Tomczak, Katarzyna; Kulcenty, Katarzyna; Płoski, Rafał; Biecek, Przemysław; Esteller, Manel; Shah, Parantu K.; Rai, Kunal; Wiznerowicz, Maciej

doi:http://dx.doi.org/10.1016/j.stemcr.2017.10.031

TRIM28 and Interacting KRAB-ZNFs control self-renewal of human pluripotent stem cells through epigenetic repression of pro-differentiation genes

Citation

Oleksiewicz U, Gładych M, Raman AT, Heyn H, Mereu E, Chlebanowska P et al. TRIM28 and Interacting KRAB-ZNFs Control Self-Renewal of Human Pluripotent Stem Cells through Epigenetic Repression of Pro-differentiation Genes. Stem Cell Reports. 2017 Dec 12;9(6):2065-80. DOI: 10.1016/j.stemcr.2017.10.031

Abstract

Reprogramming to induced pluripotent stem cells (iPSCs) and differentiation of pluripotent stem cells (PSCs) are regulated by epigenetic machinery. Tripartite motif protein 28 (TRIM28), a universal mediator of Krüppel-associated box domain zinc fingers (KRAB-ZNFs), is known to regulate both processes; however, the exact mechanism and identity of participating KRAB-ZNF genes remain unknown. Here, using a reporter system, we show that TRIM28/KRAB-ZNFs alter DNA methylation patterns in addition to H3K9me3 to cause stable gene repression during reprogramming. Using several expression datasets, we identified KRAB-ZNFs (ZNF114, ZNF483, ZNF589) in the human genome that maintain pluripotency. Moreover, we identified target genes repressed by these KRAB-ZNFs. Mechanistically, we demonstrated that these KRAB-ZNFs directly alter gene expression of important developmental genes by modulating H3K9me3 and DNA methylation of their promoters. In summary, TRIM28 employs KRAB-ZNFs to evoke epigenetic silencing of its target differentiation genes via H3K9me3 and DNA methylation.