A team of scientists from Genome Institute of Singapore (GIS) of the Agency for Science, Technology and Research (A*STAR) have shown how proteins involved in controlling genes work together to carry out their functions in stem cells and demonstrated for the very first time, how they can change interaction partners to make other types of cells. The work highlighted the collaborative nature of modern biology in which techniques and knowledge from bioinformatics analysis, structural biology, biochemistry and stem cell molecular biology were used together to find the specific amino acid within the protein that facilitated the molecular switch between stem cells and other types of cells. This discovery, published in the journal Stem Cells, has implications for generating stem cells more efficiently for biomedical applications and could help facilitate the development of treatments for diseases such as diabetes, Parkinson’s disease, and Huntington’s disease.
Dr Larry Stanton, Deputy Director for Research Affairs and Senior Group Leader of the Stem Cell and Developmental Biology department at GIS, together with Dr Prasanna Kolatkar, Dr Ralf Jauch, Dr Irene Aksoy and other colleagues from GIS, were able to take a protein, Sox17, which normallymakes gut cells, and convert it into making stem cells by changing a single amino acid. Significantly, the “new” Sox17 protein was able to make stem cells at five times the normal rate. The scientists were also able to take Sox2, a protein that normally creates stem cells and a close relative of Sox17, and convert it into making gut cells.
Dr Larry Stanton, one of the co-leaders of the project, said, “This research is a modification of the old theory that there are few native transcription factors which can help to make induced pluripotent stem cells. We show that one can take a transcription factor without IPS cell forming activity and in fact make it much more potent.”
Dr Prasanna Kolatkar, Dr Stanton’s partner in the research, “This is the first time inter-conversion of cell developmental programs has been demonstrated. Furthermore, this functional switch change was implemented by mutating a single amino acid thus showing the atomic level of understanding of the mechanism. There are many groups worldwide working on aspects of transcription factors and stem cells, as well as other groups focusing on the biochemistry and structural biology of transcription factors. What distinguishes our group is the unique integrative and collaborative science at GIS enabling us to bridge the gap between the two disciplines to study the science of transcription factors in stem cells.”
“This is an elegant study combining a range of approaches from bioinformatics to in vivo studies to switch protein functions with a tweak of just a single amino acid,” said Dr Ian Chambers, Professor of Pluripotent Stem Cell Biology at the University of Edinburgh. “By carefully comparing the biochemical properties of one of the keepers of pluripotent identity, Sox2 and the related pluripotency destroying factor, Sox17, Jauch and co-workers have made the stunning discovery that these divergent biological functions are caused largely by the identity of a single amino acid side chain in the DNA binding domain of the Sox proteins that interfaces with the transcription factor Oct4 and determines the selectivity of the Oct4/Sox binary complex for DNA. This is precisely the type of analysis that will be required to obtain the deep understanding of control of stem cell identity that is absolutely essential if we are to properly and safely use pluripotent stem cells for regenerative strategies.”
Dr Alan Colman, Executive Director of the Singapore Stem Cell Consortium at the Institute of Medical Biology, A*STAR, said, “Transcription factor (TFs) interactions with genomic DNA are one of the main elements that define cell identity during development and in adult organisms. One of the mysteries of the field is how structurally similar TFs can have very diverse effects. In a remarkable piece of work that combines diverse techniques such as X-ray crystallography, gene mutagenesis and functional analysis, my colleagues at the A*STAR Genome Institute and the Nanyang Technological University show that the change of a single amino acid can cause TFs to assume a completely different functional character.”
Continued Dr Colman, “This piece of truly elegant and insightful work is evidence of what can happen when talent from diverse fields come together to achieve breakthroughs in research. I am confident that scientists at A*STAR will continue to step across the boundaries of traditional research disciplines and produce exciting and groundbreaking work as Singapore strives towards being Asia’s Innovation Capital.”
Notes to the Editor:
The research findings described in the press release can be found in the 2011 advance online issue of Stem Cell under the title “Conversion of Sox17 into a Pluripotency Reprogramming Factor by Re-engineering its Association with Oct4 on DNA”.
Ralf Jauch1#, Irene Aksoy2#, Andrew Paul Hutchins2,3#, Calista Keow Leng Ng1,4, Xian Feng Tian2, Jiaxuan Chen2, Paaventhan Palasingam1, Paul Robson2,5, Lawrence W. Stanton2,5* and Prasanna R Kolatkar1,5*
1 Laboratory for Structural Biochemistry, Genome Institute of Singapore
60 Biopolis St, Singapore 138672
2 Stem Cell and Developmental Biology, Genome Institute of Singapore
60 Biopolis St, Singapore 138672
3 Current address: Immunology Frontier Research Centre, Osaka University, 3-1
Yamadaoka, Suita, Osaka, Japan, 565-0871
4 School of Biological Sciences, Nanyang Technological University, 50 Nanyang
Avenue, Singapore 639798
5 Department of Biological Sciences, National University of Singapore, 117543
# Equal contribution
*Corresponding authors : Lawrence W. Stanton, Ph.D., and Prasanna R. Kolatkar, Ph.D., Genome Institute of Singapore,
60 Biopolis Street #02-01, 138672 Singapore. Phone: +65 6808 8006 ; Fax: 6808 8291; e-mail: firstname.lastname@example.org or email@example.com
About the Genome Institute of Singapore
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)
The Agency for Science, Technology and Research (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 six consortia & centres, 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 more information, please contact:
Winnie Serah Lim (Ms)
Genome Institute of Singapore
Tel: (65) 6808 8013
Prudence Yeo (Ms)
Genome Institute of Singapore
Tel: (65) 6808 8010