Stem Cell Reports
Volume 9, Issue 6, 12 December 2017, Pages 2065-2080
Journal home page for Stem Cell Reports

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

https://doi.org/10.1016/j.stemcr.2017.10.031Get rights and content
Under a Creative Commons license
open access

Highlights

  • Upon reprogramming KRAB-repressor evokes stable silencing of its target genes

  • KRAB-ZNFs repress target genes required for differentiation of pluripotent cells

  • KRAB-ZNFs are crucial for the maintenance of pluripotency of human stem cells

  • TRIM28/KRAB-ZNFs repress developmental genes through H3K9 and de novo DNA methylation

Summary

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.

Keywords

reprogramming
induced pluripotent stem cells
epigenetics
TRIM28
KRAB-ZNF repressors
differentiation

Cited by (0)

17

Co-first author