ChIA-PET 3D Mapping of Human Genome Provides More Clues into Human Pathology

A new discovery is crucial to determining how human genes work together, and should transform how transcription regulation and coordination takes place in human cells.

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, demonstrating how genes interact and influence each other, even when they are located far away from each other. The GIS is a research institute under the umbrella of the Agency for Science, Technology, and Research (A*STAR).

Using a genomic technology devised by Dr. Ruan and his team, called ChIA-PET (chromatin interaction analysis with paired-end tag sequencing), the Singapore-led international group, which is part of the ENCODE (ENCyclopedia Of DNA Elements) consortium, revealed some of the essential 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 organized 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.” 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.

GIS’ executive director Prof. Huck Hui NG said, “This is an important study that sheds light on the complex regulation of gene expression. Dr. 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 (Walnut Creek, CA, USA). “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 revealed in three-dimensional space that genes separated linearly by vast distances in the human genome could 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 that was awarded to Dr. Ruan’s team by the US National Human Genome Research Institute (NHGRI), an institute belonging to the National Institutes of Health (NIH; Bethesda, MD, USA). The project was set up in 2003 with the goal 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. Up to now, Dr. Ruan’s team has received over USD 2 million towards this project.

The research findings were published January 19, 2011, in the advanced online issue of the journal Cell.

Other institutions involved in the project include: program in computational biology and departments of molecular, cellular and developmental biology, Yale University (New Haven, CT, USA); the department of molecular and medical pharmacology at the University of California, Los Angeles (UCLA; USA); Cold Spring Harbor Laboratory (Cold Spring Harbor, NY, USA); division of biology, California Institute of Technology (Pasadena, CA, USA); and the College of Life Sciences, Huazhong Agricultural University (Wuhan, China).

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. 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.

The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for Singapore. A*STAR oversees 14 biomedical sciences and physical sciences and engineering research institutes, and six consortia and centers, located in Biopolis and Fusionopolis as well as their immediate vicinity.

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Genome Institute of Singapore
Yale University
University of California, Los Angeles