A PRC2-Dependent Repressive Role of PRDM14 in Human Embryonic Stem Cells and Induced Pluripotent Stem Cell Reprogramming

被引：61

作者：

Chan, Yun-Shen ^{[1
,2
]}

Goeke, Jonathan ^{[1
,3
]}

Lu, Xinyi ^{[1
,4
]}

Venkatesan, Nandini ^{[5
]}

Feng, Bo ^{[6
]}

Su, I-Hsin ^{[5
]}

Ng, Huck-Hui ^{[1
,2
,4
,5
,7
]}

机构：

[1] Genome Inst Singapore, Gene Regulat Lab, Singapore 138672, Singapore

[2] Max Planck Inst Mol Genet, Grad Sch Integrat Sci & Engn, D-14195 Berlin, Germany

[3] Max Planck Inst Mol Genet, Dept Computat Mol Biol, D-14195 Berlin, Germany

[4] Nanyang Technol Univ, Dept Biol Sci, Singapore 637551, Singapore

[5] Nanyang Technol Univ, Div Mol Genet & Cell Biol, Sch Biol Sci, Singapore 637551, Singapore

[6] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China

[7] Natl Univ Singapore, Dept Biochem, Singapore 117548, Singapore

来源：

STEM CELLS | 2013年 / 31卷 / 04期

关键词：

PRDM14; PRC2; Embryonic stem cells; Reprogramming;

D O I：

10.1002/stem.1307

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

PRDM14 is an important determinant of the human embryonic stem cell (ESC) identity and works in concert with the core ESC regulators to activate pluripotency-associated genes. PRDM14 has been previously reported to exhibit repressive activity in mouse ESCs and primordial germ cells; and while PRDM14 has been implicated to suppress differentiation genes in human ESCs, the exact mechanism of this repressive activity remains unknown. In this study, we provide evidence that PRDM14 is a direct repressor of developmental genes in human ESCs. PRDM14 binds to silenced genes in human ESCs and its global binding profile is enriched for the repressive trimethylation of histone H3 lysine 27 (H3K27me3) modification. Further investigation reveals that PRDM14 interacts directly with the chromatin regulator polycomb repressive complex 2 (PRC2) and PRC2 binding is detected at PRDM14-bound loci in human ESCs. Depletion of PRDM14 reduces PRC2 binding at these loci and the concomitant reduction of H3K27me3 modification. Using reporter assays, we demonstrate that gene loci bound by PRDM14 exhibit repressive activity that is dependent on both PRDM14 and PRC2. In reprogramming human fibroblasts into induced pluripotent stem cells (iPSCs), ectopically expressed PRDM14 can repress these developmental genes in fibroblasts. In addition, we show that PRDM14 recruits PRC2 to repress a key mesenchymal gene ZEB1, which enhances mesenchymal-to-epithelial transition in the initiation event of iPSC reprogramming. In summary, our study reveals a repressive role of PRDM14 in the maintenance and induction of pluripotency and identifies PRDM14 as a new regulator of PRC2. STEM CELLS 2013;31:682692

引用

页码：682 / 692

页数：11

共 45 条

[1] Evans M.J., Kaufman M.H., Establishment in culture of pluripotential cells from mouse embryos, Nature, 292, pp. 154-156, (1981)
[2] Thomson J.A., Itskovitz-Eldor J., Shapiro S.S., Et al., Embryonic stem cell lines derived from human blastocysts, Science, 282, (1998)
[3] Yamanaka S., Blau H.M., Nuclear reprogramming to a pluripotent state by three approaches, Nature, 465, pp. 704-712, (2010)
[4] Chien K.R., Regenerative medicine and models of human disease, Nature, 453, pp. 302-305, (2008)
[5] Young R.A., Control of the embryonic stem cell fate, Cell, 144, pp. 940-954, (2011)
[6] Loh Y.H., Wu Q., Chew J.L., Et al., The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells, Nat Genet, 38, pp. 431-440, (2006)
[7] Boyer L.A., Lee T.I., Cole M.F., Et al., Core transcriptional regulatory circuitry in human embryonic stem cells, Cell, 122, pp. 947-956, (2005)
[8] Boyer L.A., Plath K., Zeitlinger J., Et al., Polycomb complexes repress developmental regulators in murine embryonic stem cells, Nature, 441, pp. 349-353, (2006)
[9] Lee T.I., Jenner R.G., Boyer L.A., Et al., Control of developmental regulators by polycomb in human embryonic stem cells, Cell, 125, pp. 301-313, (2006)
[10] Leeb M., Pasini D., Novatchkova M., Et al., Polycomb complexes act redundantly to repress genomic repeats and genes, Genes Dev, 24, pp. 265-276, (2010)

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