In this week's NATURE, Genome Institute of Singapore (GIS) scientists report a technological advance 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.
The technology is ChIA-PET (Chromatin Interaction Analysis using Paired End Tag sequencing). Chromatin is a complex combination of DNA and proteins that make up chromosomes.
"Many studies have found that regions of the genome which are not near genes are very important in controlling disease," said Melissa Fullwood, Ph.D., first author of the research paper and member of a team of GIS scientists led by Yijun Ruan, Ph.D., Senior Group Leader and Associate Director of Genomic Technologies, and Senior Research Scientist Edwin Cheung, Ph.D.
"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," Dr. Fullwood added.
"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,'" she said.
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 that 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 interactions.
Using the oestrogen receptor-α (ERα) as a model, the GIS 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.
"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," said Edison Liu, M.D., Executive Director of GIS, one of the research institutes sponsored by Singapore's Agency for Science, Technology and Research (A*STAR).
"The study represents a true scientific tour de force. It shows a massive genome wide scale the interactions between a specific set of enhancers and the genes they regulate. The approach and results shown here will certainly be well received by the large community studying gene regulation," said Edward Rubin, M.D., Ph.D., Director of the Genomics Division at the Lawrence Berkeley National Laboratory, University of California, Berkeley, and Director of the U.S. Department of Energy Joint Genome Institute. Dr. Rubin is a member of the GIS Scientific Advisory Board.
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. Crucial for unravelling the mechanisms of genome control during cell differentiation, ChIA-PET and the chromatin interaction map may 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 Yijun Ruan, Ph.D., and Chia-Lin Wei, Ph.D.
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).
Notes to reporters:
The research findings are reported in the Nov. 5, 2009 issue of NATURE in a paper titled, "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 Sung1,3, Edison T. Liu1, Chia-Lin Wei1, Edwin Cheung1,4,5,*, Yijun Ruan1, 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
Yijun Ruan, Ph.D. 65 6478 8073;firstname.lastname@example.org and
Edwin Cheung, PhD: 65 6478 8184; email@example.com
GENOME INSTITUTE OF SINGAPORE: www.gis.a-star.edu.sg
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.
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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.
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