14 March 2013 -- Scientists at the Agency for Science, Technology and Research’s (A*STAR) Genome Institute of Singapore (GIS) have discovered that key gene regulators work in pairs to trigger stem cells to differentiate into specific cell types. Furthermore, they showed that selective partnering of the regulators result in uniquely specified developmental outcomes.
An embryo develops from a single cell to a complex, interconnected assemblage of multiple cell types in the adult organism, such as the muscles, nerves, lungs and heart. The fates of embryonic cells as they differentiate into specialized adult cells require tightly regulated expression of hundreds of genes; each cell type being regulated by a unique and specific pattern of gene expression. Transcription factors are master regulators of gene expression and have been implicated as key players in the appropriate specification embryo development. They do this by binding to DNA thereby “turning on” or “turning off” nearby genes. What is less clear is how these transcription factors select specific sets of genes for activation and repression.
A recent study by scientists from GIS has discovered that it takes a pair of transcription factors, working tightly together, to orchestrate key decisions in embryo development. The discovery was published in the prestigious EMBO Journal.
The study, a multidisciplinary collaborative effort, established that the transcription factor Oct4 alternatively partners with two related factors, Sox2 or Sox17. This paper, together with a related paper published in the journal Stem Cells in 2011 (“Conversion of Sox17 into a reprogramming factor by re-engineering its association with Oct4 on DNA.”), makes a key discovery about how the selective partnering of the two transcription factors can lead to very different developmental outcomes.
Lead author Dr. Lawrence Stanton said, “This work was a unique collaboration between scientists hailing from different areas of expertise – computational biology, cell biology, developmental biology and biochemistry. The unique line of research was only possible by the interdisciplinary efforts of these scientists.”
Co-lead author Dr. Prasanna Kolatkar said, “Our previous work described how re-engineering of developmental proteins through a single site change results in functions of proteins Sox2 and Sox17 becoming inter-converted – thus the decision to stay as a stem cell or differentiate is flipped through a single amino acid change. This study uses a genome-wide approach to validate this concept, and moreover leads to novel genes potentially involved in primitive endoderm formation.”
"This work identified a novel regulatory switch from pluripotency to cell-lineage specific differentiation. It is remarkable that a single pluripotency factor, Oct4, was found to influence diverse cellular processes. This key discovery illustrates the complexity in the regulation of pluripotency programme in embryonic stem cells," said GIS Executive Director Prof Ng Huck Hui.
The research findings described in the press release can be found in the 8 March 2013 advance online issue of The EMBO Journal (European Molecular Biology Organization) under the title “Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm”.
Irene Aksoy1,#, Ralf Jauch2,#, Jiaxuan Chen1, Mateusz Dyla2, Ushashree Divakar1, Gireesh K. Bogu1, Roy Teo1,Calista Keow Leng Ng2,3, Wishva Herath1, Andrew P. Hutchins1,4, Paul Robson1,5, Prasanna R Kolatkar2,5* and Lawrence W. Stanton1, 3,5*
1. Stem Cell and Developmental Biology, and
2. Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis St, Singapore 138672
3. School of Biological Sciences, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798
4. Immunology Frontier Research Centre, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan, 565-0871
5. Department of Biological Sciences, National University of Singapore, Singapore 117543
# Equal contribution.
* Co-corresponding authors:
Lawrence W. Stanton (firstname.lastname@example.org) and
Prasanna R Kolatkar (email@example.com)
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About the Genome Institute of Singapore (GIS)
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.
Please visit www.gis.a-star.edu.sg.
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 fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.
In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore’s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.
A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR’s research entities as well as a growing number of corporate laboratories.
Please visit www.a-star.edu.sg.