TRIM28 and Interacting KRAB-ZNFs Control Self-Renewal of Human Pluripotent Stem Cells through Epigenetic Repression of Pro-differentiation Genes

• Published in: Stem cell reports
• Main Authors: Oleksiewicz, Urszula, Gladych, Marta, Raman, Ayush T, Heyn, Holger, Mereu, Elisabetta, Chlebanowska, Paula, Andrzejewska, Anastazja, Sozanska, Barbara, Samant, Neha, Fak, Katarzyna, Auguscik, Paulina, Kosinski, Marcin, Wroblewska, Joanna P, Tomczak, Katarzyna, Kulcenty, Katarzyna, Ploski, Rafal, Biecek, Przemyslaw, Esteller, Manel, Shah, Parantu K, Rai, Kunal, Wiznerowicz, Maciej
• Format: Journal Article
• Language: English
• Published: Elsevier 01.12.2017
• Subjects: ADN; Cèl·lules mare; DNA; Epigenetics; Epigenètica; Stem cells
• ISSN: 2213-6711; 2213-6711

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 Kruppel-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.