Scientists at the Genome Institute of Singapore (GIS), a biomedical research institute of the Agency for Science, Technology and Research (A*STAR), and their colleagues from the National University of Singapore, Nanyang Technological University, Duke-NUS Graduate Medical School and Princeton University have recently discovered that viruses that ‘invaded’ the human genome millions of years ago have changed the way genes get turned on and off in human embryonic stem (ES) cells.

The study provides definitive proof of a theory that was first proposed in the 1950s by Nobel Laureate in physiology and medicine, Barbara McClintock, who hypothesized that transposable elements, mobile pieces of the genetic material (DNA), such as viral sequences, could be “control elements” that affect gene regulation once inserted in the genome.

This finding is an important contribution to the advancement of stem cell research and to its potential for regenerative medicine. Led by GIS Senior Group Leader Dr Guillaume Bourque, the study was published in Nature Genetics on June 6, 2010.

Through the use of new sequencing technologies, the scientists studied the genomic locations of three regulatory proteins (OCT4, NANOG and CTCF) in human and mouse embryonic stem (ES) cells.  Interestingly, while the scientists found a lot of similarities, they also found many differences in the methods and the types of genes that are being regulated in humans. In particular, it was discovered that specific types of viruses that inserted themselves in the human genomes millions of years ago have dramatically changed the gene regulatory network in human stem cells.

"This study is a computational and experimental tour de force. It provides undeniable evidence that some transposable elements, which are too often dismissed as merely junk DNA, are key components of a regulatory code underlying human development," said Dr Cedric Feschotte, Associate Professor of the University of Texas Arlington.

The comparisons between the human and mouse model system in the study of gene regulatory networks help to advance the understanding of how stem cells differentiate into various cell types of the body. “This understanding is crucial in the improved development of regenerative medicine for diseases such as Parkinson’s disease and leukaemia,” said Dr Bourque. “Despite the advantages of using mouse ES cells in the study of gene regulatory networks, further research must focus more directly on human stem cells. This is due to the inherent challenges of converting the results of studies done from one species to that of the next. More research will need to be done in both human and non-human primate stem cells for findings on stem cells to be used in clinical application.”

Prof Raymond L. White, PhD, Rudi Schmid Distinguished Professor of Neurology, University of California said, “The paper reports very exciting new findings that establish a new and fundamentally distinct mechanism for the regulation of gene expression. By comparing the genomes of mouse with human, the scientists were able to show that the binding sites for gene regulatory factors are very often not in the same place between the two species. This by itself would be very surprising, but the investigators go further and demonstrate that many of the sites are imbedded within a class of DNA sequences called “transposable” elements because of their ability to move to new places in the genome. There are a number of such elements believed to be the evolutionary remnants of viral genomes, but it was very surprising to learn that they were carrying binding sites for regulatory elements to new locations. These changes in regulation would be expected to create major changes in the organisms which carry them. Indeed, many think that regulatory changes are at the heart of speciation and may have played a large role in the evolution of humans from their predecessors. This is likely to be a landmark paper in the field.”

Dr Eddy Rubin, Director of the U.S. Department of Energy Joint Genome Institute and Director of the Genomics Division at Lawrence Berkeley National Laboratory in Berkeley added, "This study using a comparative genomics strategy discovered important human specific properties of the regulatory network in human ES cells. This information is significant and should contribute to helping move the regenerative medicine field forward.”

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Notes to the Editor:
Research publication:
The research findings described in the press release can be found on the Advance Online Publication (AOP) on Nature Genetics' website under the title “TRANSPOSABLE ELEMENTS HAVE REWIRED THE CORE REGULATORY NETWORK OF HUMAN EMBRYONIC STEM CELLS”.
    
Authors:
Galih Kunarso1,2, Na-Yu Chia3,4, Justin Jeyakani1, Catalina Hwang1,5, Xinyi Lu3,6, Yun-Shen Chan3,7, Huck-Hui Ng3,4,6,7,8, Guillaume Bourque1

1) Computational & Mathematical Biology, Genome Institute of Singapore, Singapore  138672
2) Duke-NUS Graduate Medical School, Singapore 169857
3) Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672
4) School of Biological Sciences, Nanyang Technological University, Singapore 639798
5) Princeton University, Princeton, New Jersey 08544, USA
6) Dept of Biological Sciences, National University of Singapore, Singapore 117543
7) Graduate School for Integrative Sciences & Engineering, National University of  Singapore, Singapore 117543
8) Dept of Biochemistry, National University of Singapore, Singapore 117543

Correspondence should be addressed to Guillaume Bourque (Tel: +65 6808 8197; Email: bourque@gis.a-star.edu.sg)


About the Genome Institute of Singapore
www.gis.a-star.edu.sg

The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

About the Agency for Science, Technology and Research (A*STAR)
www.a-star.edu.sg

A*STAR is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and nine consortia & centres, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.

For enquiries, please contact the following:
Genome Institute of Singapore
Winnie Serah Lim
Corporate Communications
Tel:    (65) 6808 8013
           (65) 9730 7884
Email: limcp2@gis.a-star.edu.sg

Prudence Yeo Jiajia
Corporate Communications
Tel:    (65) 6808 8010
           (65) 9668 4074
Email: yeojp@gis.a-star.edu.sg

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