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Ludwig Cancer Research to play key role in NIH's 4D Nucleome Program

Oct 5, 2015

October 5, 2015, New York, NY – Ludwig Cancer Research scientist Bing Ren has been tapped to play a key role in a major initiative launched by the US National Institutes of Health—a 4D Nucleome Program that will transform how we read and interpret the genome.

The program is slated to receive $120 million over the next five years, depending on future appropriations and reviews of progress. It will be composed of six separate but interrelated initiatives that encompass 29 awards to 24 institutions throughout the United States. Bing Ren is a principal investigator (PI) for a part of one of those initiatives—the Nuclear Organization and Function Interdisciplinary Consortium—which has been awarded $8.6 million. He is also a PI in the $20.2 million 4D Nucleome Program Organizational Hub that is to be based on the University of California, San Diego campus.

“Researchers typically read the genome as a linear recipe book of genes and regulatory sequences that have been packaged into our 46 chromosomes, and the approach continues to yield valuable biological insights,” said Ren, who is a member of the Ludwig Institute for Cancer Research and professor of cellular and molecular medicine at the University of California, San Diego School of Medicine. “But it has long been clear that many biological phenomena and diseases stem from DNA sequences that lie outside genes, which activate, silence or modulate gene expression. These intervening sequences hold remarkable sway over how chromosomes are structured. We now have the technology to map the dynamic relationship between chromosomal structure and gene expression on a genome-wide scale. These patterns can be linked to the biological features of different types of cells and the origins of complex diseases.”

The 4D Nucleome Program will pin down the relationship between gene expression and the three-dimensional structure of chromosomes, and how the two play out and change over time. This is called the fourth dimension. 

A system of chemical or epigenetic tagging that selectively modifies both DNA and its protein packaging determines which genes are made available for reading, how avidly they are read and which ones are temporarily (or permanently) switched off. Stretches of chromosomes that are tagged to be silent are typically folded up and sequestered from the cell’s gene-reading machinery. Those bearing genes that are expressed are, conversely, held open and available. These patterns give resting chromosomes a subtle and layered structure that is directly related to gene expression.

As former director of one of four national Reference Epigenome Mapping Centers of the NIH’s Epigenome Roadmap Program, Ren led the development of sophisticated methods to read epigenetic tags on a genomic scale and link them to the three-dimensional structures of chromosomes. He and his colleagues reported in Nature earlier this year how epigenetic tags correspond to the regulation of gene expression and the structures of chromosomes—and how these collectively differ between different types of cells.

Ren will now bring that expertise to the 4D Nucleome Program. The data generated by this project will enable a deeper understanding of normal biology as well as disease. Cancer, for example, is driven not only by mutations to coding gene sequences but to noncoding ones as well, and it is invariably marked by wholesale alterations in the epigenomic landscape.

The Organizational Hub at UC San Diego will—in collaboration with another one of the six program initiatives—create a web portal and integrate the efforts of all the 4D Nucleome Program’s funded initiatives. The Nuclear Organization and Function Interdisciplinary Consortium will create research centers at several institutions, including UC San Diego, and support interdisciplinary teams to create the next generation of high-throughput technologies for the creation of dynamic three-dimensional maps of mammalian genomes.