TY - JOUR
T1 - TRIM28 and Interacting KRAB-ZNFs Control Self-Renewal of Human Pluripotent Stem Cells through Epigenetic Repression of Pro-differentiation Genes
AU - Oleksiewicz, Urszula
AU - Gładych, Marta
AU - Raman, Ayush T.
AU - Heyn, Holger
AU - Mereu, Elisabetta
AU - Chlebanowska, Paula
AU - Andrzejewska, Anastazja
AU - Sozańska, Barbara
AU - Samant, Neha
AU - Fąk, Katarzyna
AU - Auguścik, Paulina
AU - Kosiński, Marcin
AU - Wróblewska, Joanna P.
AU - Tomczak, Katarzyna
AU - Kulcenty, Katarzyna
AU - Płoski, Rafał
AU - Biecek, Przemysław
AU - Esteller, Manel
AU - Shah, Parantu K.
AU - Rai, Kunal
AU - Wiznerowicz, Maciej
N1 - Funding Information:
This work was supported by the Foundation for Polish Science Welcome program (grant no. 2010-3/3 to M.W.), the Greater Poland Cancer Center (Poznań, Poland) intramural funds, in part by PL-Grid Infrastructure, University of Texas at MD Anderson Cancer Center (MDACC) start-up funds to K.R., and Core grant CA016672 to the DNA core facility at MDACC. H.H. is a Miguel Servet ( CP14/00229 ) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). We would like to thank Prof. Giulio Draetta from the MDACC for his help with the RNA-seq analyses. We are also grateful to Prof. Gustavo Mostoslavsky from the Boston University School of Medicine for his kind gift of the pHAGE2-hSTEMCCA-EF1α-loxp plasmid used for the induction of pluripotency and to Dr. Patrycja Czerwińska for the gift of pWPXL-flagTRIM28 vector.
Funding Information:
This work was supported by the Foundation for Polish Science Welcome program (grant no. 2010-3/3 to M.W.), the Greater Poland Cancer Center (Poznań Poland) intramural funds, in part by PL-Grid Infrastructure, University of Texas at MD Anderson Cancer Center (MDACC) start-up funds to K.R., and Core grant CA016672 to the DNA core facility at MDACC. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII). We would like to thank Prof. Giulio Draetta from the MDACC for his help with the RNA-seq analyses. We are also grateful to Prof. Gustavo Mostoslavsky from the Boston University School of Medicine for his kind gift of the pHAGE2-hSTEMCCA-EF1α-loxp plasmid used for the induction of pluripotency and to Dr. Patrycja Czerwińska for the gift of pWPXL-flagTRIM28 vector.
Publisher Copyright:
© 2017 The Authors
PY - 2017/12/12
Y1 - 2017/12/12
N2 - 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. Oleksiewicz et al. report that, during somatic cells reprogramming to iPSCs, KRAB-ZNF target genes become stably silenced through H3K9 and DNA methylation. Endogenous KRAB-ZNFs overexpressed in iPSCs, together with TRIM28, were found to participate in the maintenance of pluripotency by targeting and repressing differentiation genes in PSCs.
AB - 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. Oleksiewicz et al. report that, during somatic cells reprogramming to iPSCs, KRAB-ZNF target genes become stably silenced through H3K9 and DNA methylation. Endogenous KRAB-ZNFs overexpressed in iPSCs, together with TRIM28, were found to participate in the maintenance of pluripotency by targeting and repressing differentiation genes in PSCs.
KW - KRAB-ZNF repressors
KW - TRIM28
KW - differentiation
KW - epigenetics
KW - induced pluripotent stem cells
KW - reprogramming
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U2 - 10.1016/j.stemcr.2017.10.031
DO - 10.1016/j.stemcr.2017.10.031
M3 - Article
C2 - 29198826
AN - SCOPUS:85035749403
SN - 2213-6711
VL - 9
SP - 2065
EP - 2080
JO - Stem Cell Reports
JF - Stem Cell Reports
IS - 6
ER -