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  current news   Press   selected story    
     
  10 June 2016  
 
RNA Interference Reveals Phase-Specific Global Regulators of Human Somatic Cell Reprogramming
 
 




Authors
Cheng-Xu Delon Toh1,2,24, Jun-Wei Chan1,24, Zheng-Shan Chong1,24, Hao Fei Wang1,3, Hong Chao Guo1,4, Sandeep Satapathy1, Dongrui Ma5, Germaine Yen Lin Goh6, Ekta Khattar7, Lin Yang8,9,10, Vinay Tergaonkar7,11, Young-Tae Chang12,13, James J. Collins10,14,15.16, George Q. Daley10,17,18.19,20, Keng Boon Wee21,22, Chadi A. EL Farran1,3, Hu Li23,*, Yoon-Pin Lim2,11,22,**, Frederic A. Bard6,11 and Yuin-Han Loh1,2,3,***

1   Epigenetics and Cell Fates Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis     Drive Proteos, Singapore 138673, Singapore
2   NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28     Medical Drive, Singapore 117456, Singapore
3   Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore     117543, Singapore
4   College of Life Sciences, Nankai University, Tianjin 300071, China
5   Research and Development Unit (RDU), National Heart Centre Singapore, 5th Hospital Drive,     Singapore 169609, Singapore
6   Membrane Traffic Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive     Proteos, Singapore 138673, Singapore
7   Division of Cancer Genetics and Therapeutics, Laboratory of NF-kB Signaling, A*STAR Institute of     Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore
8   Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
9   Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
10  Howard Hughes Medical Institute, Boston, MA 02114, USA
11  Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,     Singapore 117545, Singapore
12  Lab of Bioimaging Probe Development, A*STAR Singapore Bioimaging Consortium (SBIC), 11 Biopolis     Way Helios, Singapore 138673, Singapore
13  Department of Chemistry and MedChem Program, Life Sciences Institute, National University of     Singapore, 3 Science Drive 3, Singapore 117543, Singapore
14  Institute for Medical Engineering and Science Department of Biological Engineering, and Synthetic     Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
15  Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA
16  Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
17  Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children’s     Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA
18  Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA     02115, USA
19  Harvard Stem Cell Institute, Boston, MA 02115, USA
20  Manton Center for Orphan Disease Research, Boston, MA 02115, USA
21  A*STAR Institute of High Performance Computing (IHPC), Connexis, Singapore 138632, Singapore
22  A*STAR Bioinformatics Institute, Singapore 138671, Singapore
23  Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental     Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
24  Co-first author
*Correspondence: li.hu@mayo.edu
**Correspondence: bchlyp@nus.edu.sg
***Correspondence: yhloh@imcb.a-star.edu.sg

Published online ahead of print in Cell Reports on 9 June 2016.

Abstract
Incomplete knowledge of the mechanisms at work continues to hamper efforts to maximize reprogramming efficiency. Here, we present a systematic genome-wide RNA interference screen to determine the global regulators during the early stages of human reprogramming. Our screen identifies functional repressors and effectors that act to impede or promote the reprogramming process. Repressors and effectors form close interacting networks in pathways including RNA processing, G-protein signaling, protein ubiquitination and chromatin modification. Combinatorial knockdown of 5 repressors (SMAD3, ZMYM2,SFRS11, SAE1, ESET) synergistically resulted in close to 85% TRA-1-60 positive cells. Removal of the novel splicing factor SFRS11 during reprogramming is accompanied by rapid acquisition of pluripotency-specific spliced forms. Mechanistically, SFRS11 regulates exon skipping and mutually exclusive splicing of transcripts in genes involved in cell differentiation, mRNA splicing and chromatin modification. Our study provides insights into the reprogramming process, which comprises of comprehensive and multi-layered transcriptional, splicing and epigenetic machineries.



For more information on Jonathan LOH's laboratory, please click here.