Singapore Scientists Lead in 3D Mapping of Human Genome to Help Understand Human Diseases

Genome Institute of Singapore's (GIS) Associate Director of Genomic Technologies, Dr Yijun RUAN, led a continuing study on the human genome spatial/structural configuration, revealing how genes interact/communicate and influence each other, even when they are located far away from each other.

The discovery was published in Cell, on 19 January 2012. The GIS is a research institute under the umbrella of the Agency for Science, Technology and Research (A*STAR).

Using a genomic technology invented by Dr Ruan and his team, called ChIA-PET, the Singapore-led international group, which is part of the ENCODE (ENCyclopedia Of DNA Elements) consortium, uncovered some of the fundamental mechanisms that regulate the gene expression in human cells.

"Scientists have always tried to understand how the large number of genes in an organism is regulated and coordinated to carry out the genetic programs encoded in the genome for cellular functions in our cells. It had been viewed that genes in higher organisms were individually expressed, while multiple related genes in low organisms like bacteria were arranged linearly together as operon and transcribed in single unit," Dr Ruan explained.

"The new findings in this study revealed that although genes in human genomes are located far away from each other, related genes are in fact organised through long-range chromatin interactions and higher-order chromosomal conformations. This suggests a topological basis akin to the bacteria operon* system for coordinated transcription regulation. This topological mechanism for transcription regulation and coordination also provides insights to understand genetic elements that are involved in human diseases."

GIS' executive director Prof Huck Hui NG said: "This is an important study that sheds light on the complex regulation of gene expression. Yijun's team continues to use the novel method of Chromatin Interaction Analysis with Paired-End-Tag sequencing to probe the higher order interactions of chromatin to discover new regulatory interactions between genes."

"This publication describes ground-breaking work by Dr Yijun Ruan and his team at Genome Institute of Singapore," added Dr Edward Rubin, Director of the Joint Genome Institute in US. "They address the fundamental question of how communication occurs between genes and their on and off switches in the human genome. Using a long range DNA mapping technology called ChIA-PET, the study reveals in three dimensional space that genes separated linearly by enormous distances in the human genome can come to lie next to each other in the cell when it is time for them to become active.

"I expect this study to move rapidly from primary scientific literature to textbooks describing for future students the operating principles of the human genome. The ChIA-PET technology, that is the telescope used in this exploration of the human genome, is an innovative and powerful molecular technology invented by Dr Ruan and his collaborators."

The ENCODE is an ongoing project which was awarded to Dr Ruan's team by the National Human Genome Research Institute (NHGRI), an institute belonging to the National Institutes of Health (NIH, USA). The project was set up in 2003 with the aim of discovering all functional elements in the human genome to gain a deeper understanding of human biology and develop new strategies for preventing and treating diseases. So far Dr Ruan's team has received over US$2 million towards this project.

*In genetics, an operon is a functioning unit of genomic DNA containing a cluster of genes under the control of a single regulatory signal or promoter.