A team of scientists at A*STAR’s Genome Institute of Singapore (GIS), led by Senior Group Leader and Associate Director of Genomic Technologies Dr Yijun Ruan and Senior Research Scientist Dr Edwin Cheung, has made a major technological breakthrough in the study of gene expression and regulation in the genome’s three-dimensional folding and looping state through the development of a novel technology called the ChIA-PET[1]. Their results were published in the November 2009 issue of the prestigious journal, Nature.

 

Ever since the human genome was found to be organized in a three-dimensional (3D) manner rather than in a two-dimensional linear fashion, scientists have been challenged to find an effective method to study the regulation of gene activity which took into account the complexities of its 3D structure. Using ChIA-PET technology, the GIS scientists have successfully met the challenge and confirmed the presence of genome-wide long-range chromatin[2] interactions.

 

Using the oestrogen receptor-α (ERα) as a model, the scientists investigated how the human genome was organized in response to oestrogen signalling to control the expression of genes in breast cancer cells. They discovered that extensive ERα-bound long-range chromatin interactions in the human genome were involved as a primary mechanism for regulating estrogen-mediated gene expression.    

 

First author of the research paper, Dr Melissa Fullwood, a PhD student when she worked on this study at the GIS, said, “Many studies have found that regions of the genome which are not near genes are very important in controlling disease. In thinking about how this can happen, many scientists hypothesized that chromatin interactions – 3-dimensional loops in DNA – might be what allow these regions to remotely talk to genes. The subsequent discovery of chromatin interactions between specific genes and specific enhancer sites generated a lot of interest to find chromatin interactions throughout the entire genome. Our study is one of the first to be able to address this ‘Holy Grail' of genomics.” Dr Fullwood was also one of three winners of the inaugural L’Oréal Singapore for Women in Science National Fellowship awards, presented in August 2009 for outstanding work by female researchers with the potential to contribute to science.

 

Executive Director of the GIS, Prof Edison Liu, said, “Our institute had been working to develop this technology to answer a fundamental question in cancer. These results show us that higher order DNA interactions on a genome scale can explain some of the contradictions in older studies. This work will pave the way for the development of highly specific anti-hormone treatments in breast cancer. “

 

 

The ChIA-PET methodology and the ERα-bound human chromatin interaction map represent the starting point of an entirely new field for scientists to study how the human genome is folded in order to communicate the codes in regulating gene expression. The discovery is crucial in unravelling the mechanisms of genome control during cell differentiation and will lead to a better understanding and control of diseases. This method was based on a revolutionary gene sequencing method known as paired-end ditag (PET) sequencing, which was pioneered in 2005 by GIS scientists, led by Senior Group Leaders Drs Yijun Ruan and Chia-Lin Wei.

 

This work has been recognized and funded by a grant from the National Institutes of Health’s (NIH) public research consortium known as ENCODE (Encyclopedia of DNA Elements).

The research findings described in the press release can be found in the November 5, 2009 issue of Nature under the title “An Oestrogen Receptor α-bound Human Chromatin Interactome”.

 

Melissa J. Fullwood¹, Mei Hui Liu¹, You Fu Pan¹, Jun Liu¹, Xu Han¹, Yusoff Bin Mohamed¹, Yuriy L. Orlov¹, Stoyan Velkov¹, Andrea Ho¹, Poh Huay Mei¹, Elaine G. Y. Chew¹, Phillips Yao Hui Huang¹, Willem-Jan Welboren², Yuyuan Han¹, Hong-Sain Ooi¹, Pramila N. Ariyaratne¹, Vinsensius B. Vega¹, Yanquan Luo¹, Peck Yean Tan¹, Pei Ye Choy¹, K. D. Senali Abayratna Wansa¹, Bing Zhao¹, Kar Sian Lim¹, Shi Chi Leow¹, Jit Sin Yow¹, Roy Joseph¹, Haixia Li¹,Kartiki V. Desai¹, Jane S. Thomsen¹, Yew Kok Lee¹, R. Krishna Murthy Karuturi¹, Thoreau Herve¹, Guillaume Bourque¹, Hendrik G. Stunnenberg², Xiaoan Ruan¹, Valere Cacheux-Rataboul¹, Wing-Kin Sung^1,3, Edison T. Liu¹, Chia-Lin Wei¹, Edwin Cheung^1,4,5,*, Yijun Ruan^{1, 4,*}

1.      Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore;

2.      Department of Molecular Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University, The Netherlands;

3.      Department of Computer Science, School of Computing, National University of Singapore, Singapore;

4.      Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;

5.      School of Biological Sciences, Nanyang Technological University, Singapore

 

^*Corresponding authors:

Yijun Ruan, PhD

Genome Institute of Singapore, 60 Biopolis, Singapore 138672

T. 65 6478 8073; F. 65 6478 9059; E. ruanyj@gis.a-star.edu.sg

 

Edwin Cheung, PhD
Genome Institute of Singapore, 60 Biopolis, Singapore 138672

T. 65 6478 8184; F. 65 6478 9003; E. cheungcwe@gis.a-star.edu.sg

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The Genome Institute of Singapore (GIS) is a member of the Agency for Science, Technology and Research (A*STAR). It is a national initiative with 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

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 seven consortia & centre, 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.

Winnie Serah Lim

Office of Corporate Communications

Tel:      (65) 6478 8013

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