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Stem Cell Reports. 2017 Dec 12;9(6):2065-2080. doi: 10.1016/j.stemcr.2017.10.031. Epub 2017 Nov 30.

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

Author information

1
Laboratory for Gene Therapy, Department of Cancer Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland.
2
Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
3
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Catalonia, Spain; CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08036, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
4
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08036, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
5
Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland; University of Life Sciences, 60-637 Poznan, Poland.
6
Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland; Adam Mickiewicz University, Biology Department, 61-614 Poznan, Poland.
7
Faculty of Mathematics and Information Science, Warsaw University of Technology, 00-602 Warsaw, Poland.
8
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
9
Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland.
10
Department of Medical Genetics, Medical University of Warsaw, 02-091 Warsaw, Poland.
11
Faculty of Mathematics and Information Science, Warsaw University of Technology, 00-602 Warsaw, Poland; Warsaw Faculty of Mathematics, Informatics, and Mechanics, University of Warsaw, 02-097 Warsaw, Poland.
12
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08908, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona 08907, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Catalonia, Spain.
13
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
14
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: krai@mdanderson.org.
15
Laboratory for Gene Therapy, Department of Cancer Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland; Laboratory for Gene Therapy, Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland. Electronic address: wiznerowicz@ump.edu.pl.

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.

KEYWORDS:

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

PMID:
29198826
PMCID:
PMC5785758
DOI:
10.1016/j.stemcr.2017.10.031
[Indexed for MEDLINE]
Free PMC Article

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