A*STAR Scientists reveal how stem cells defend against viruses

New insights to the mechanisms bring broad implications to stem cell therapy and disease diagnosis.

Left: Embryonic stem cells with silencing of viruses. Right: Removal of silencing machineries Cha1fa and Sumo2 resulting in the activation of viruses (in green)

Singapore—Scientists from the Institute of Molecular and Cell Biology (IMCB), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore, have uncovered the mechanisms which embryonic stem cells employ to inhibit virus expression. The ground-breaking discovery could potentially advance stem cell therapeutics and diagnostics.

Several stem cell types including embryonic and haematopoietic stem cells are known to be capable of suppressing the activities of infected viruses and viral DNA residing in the host genome. This characteristic property, known as proviral silencing, however, has not been fully understood. In order to study this, a team of scientists from IMCB designed a novel assay which allowed them to screen all the genes present in embryonic stem cells.

Through the screening platform, the team identified 303 genes and elucidated 148 biological processes and pathways linked to proviral silencing, suggesting that proviral silencing is controlled by coordinated mechanisms involving multiple cellular pathways. Through a comprehensive analysis, the scientists concluded that two specific genes, Chaf1a and Sumo2, are the key factors linked to proviral silencing. The findings of the study were reported in the top-tier scientific journal, Cell.

Further studies on the roles of Chaf1a and Sumo2 in stem cell proviral silencing can shed new light on stem cells and virus biology that could translate into valuable therapeutic and diagnostic applications.

Dr Jonathan Loh, Principal Investigator of IMCB, said, “This is the first detailed study on proviral silencing in embryonic stem cells, and it helped us gain a deeper understanding of stem cells and its unique proviral silencing ability. With the new insights, we can better identify the good stem cells and use them more efficiently and safely in clinical therapies. We can also devise diagnostic approaches by studying the activities of the virus DNA within stem cells in various diseased conditions.”

Prof Hong Wanjin, Executive Director of IMCB, said, “Fundamental research on human biology seeks to understand crucial biological processes occurring within humans in order to bring advancement in therapeutics and improve lives. With the growing importance of stem cell therapy, this study is a fitting example of how upstream research can potentially benefit and shape its applications.”

Notes for Editor:
The research findings described in this media release can be found in the Cell Journal, under the title, “Systematic Identification of Factors for Provirus Silencing in Embryonic Stem Cells” by Bin Xia Yang1,22, Chadi A. EL Farran1,2,22, Hong Chao Guo3,22, Tao Yu1,2,22, Hai Tong Fang1, Hao Fei Wang1,2, Sharon Schlesinger4,5, Yu Fen Samantha Seah1, Germaine Yen Lin Goh6, Suat Peng Neo7, Yinghui Li9, Matthew C. Lorincz10, Vinay Tergaonkar9,21, Tit-Meng Lim2, Lingyi Chen3, Jayantha Gunaratne7,8, James J. Collins11,12,13,14, Stephen P. Goff4,5,15, George Q. Daley14,16,17,18,19, Hu Li20, Frederic A. Bard6,21 and Yuin-Han Loh1,2

1Epigenetics and Cell Fates Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673,
2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
3College of Life Sciences, Nankai University, Tianjin 300071, China
4Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
5Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA
6Membrane Traffic Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore
7Quantitative Proteomics Group, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore
8Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
9Division 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
10Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
11Department of Biological Engineering, Synthetic Biology Center, Institute for Medical Engineering and Science, Massachusetts Institute of
Technology, Cambridge, MA 02139, USA
12Harvard-MIT Program in Health Sciences and Technology, Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA
13Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
14Howard Hughes Medical Institute, Boston, MA 02115, USA
15Howard Hughes Medical Institute, New York, NY 10032, USA
16Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children’s Hospital and Dana-Farber Cancer
Institute, Boston, MA 02115, USA
17Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
18Harvard Stem Cell Institute, Boston, MA 02115, USA
19Manton Center for Orphan Disease Research, Boston, MA 02115, USA
20Center for Individualized Medicine, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
21Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
22Co-first author

Correspondence should be addressed to Yuin-Han Loh, Epigenetics and Cell Fates Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore. E-mail: [email protected]

Full text of the Cell paper can be accessed online from: http://www.cell.com/cell/abstract/S0092-8674%2815%2901089-2

For media queries and clarifications, please contact:

Tan Yun Yun
Senior Officer, Corporate Communications
Agency for Science, Technology and Research
Tel: +65 6826 6273
Email: [email protected]

About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that spearheads economic oriented research to advance scientific discovery and develop innovative technology. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit society.

As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by contributing to societal benefits such as improving outcomes in healthcare, urban living, and sustainability.

We play a key role in nurturing and developing a diversity of talent and leaders in our Agency and Research Institutes, the wider research community and industry. A*STAR oversees 18 biomedical sciences and physical sciences and engineering research entities primarily located in Biopolis and Fusionopolis.

For more information on A*STAR, please visit www.a-star.edu.sg.

About the Institute of Molecular and Cell Biology (IMCB)
The Institute of Molecular and Cell Biology (IMCB) was launched on 23 January 1985, with its official opening ceremony held on 2 October 1987 at the National University of Singapore (NUS). It subsequently became an autonomous research institute (RI) of A*STAR, moving to Biopolis in 2004. IMCB’s vision is to be a premier cell and molecular biology institute which addresses the mechanistic basis of human diseases and its mission is to conduct cutting-edge discovery research in disease pathways; to groom early career researchers to be future leaders in research; and to collaborate with medical and industry communities for research impact. IMCB plays an important role training and recruiting scientific talents, and has contributed to the development of other research entities in Singapore. Its success in fostering a biomedical research culture in Singapore has catalysed Singapore’s transformation into an international hub for biomedical research, development and innovation.

Funded primarily by the Biomedical Research Council (BMRC) of A*STAR, IMCB’s current discovery research includes cell biology in health and disease; animal models of development & disease; cancer & stem cell genetics & genomics; and structural biology & drug discovery. IMCB’s translational research includes humanised model organisms for human diseases; systems approach for disease target identification & validation; and protein engineering & antibody development for diagnostics & therapeutics. Research activities in IMCB are supported by cutting edge infrastructure and facilities including quantitative proteomics; humanised mice; mouse models of human cancer; protein crystallography X-ray; zebrafish for drug metabolism & toxicology; advanced molecular histopathology; imaging & electron microscopy; and DNA sequencing.

For more information about IMCB, visit www.imcb.a-star.edu.sg