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A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity
Na-Yu Chia1,2,10, Yun-Shen Chan1,3,10, Bo Feng1,10, Xinyi Lu1,4, Yuriy L. Orlov5, Dimitri Moreau6, Pankaj Kumar6, Lin Yang1, Jianming Jiang1, Mei-Sheng Lau1, Mikael Huss5, Boon-Seng Soh7, Petra Kraus7, Pin Li7, Thomas Lufkin7, Bing Lim7,8, Neil D. Clarke5,9, Frederic Bard6,9 & Huck-Hui Ng1,2,3,4,9
The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology1. The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells.
1Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672
2School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551
3Graduate School for Integrative Sciences & Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456
4Dept of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543
5Computational and Systems Biology group, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672
6Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
7Stem Cell and Developmental Biology, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672
8Center for Life Sciences, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA
9Department of Biochemistry, National University of Singapore, 8 Medical Drive, Yong Loo Lin School of Medicine, Singapore 117597
10These authors contributed equally to this work.
