image: This is an illustration of an epigenome. view more
Credit: UCSD School of Medicine
Bing Ren, Ph.D., associate professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine and head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research, was recently selected as one of four grant recipients in the National Institutes of Health (NIH) Roadmap's Epigenomics Program, an initiative developed to study stable genetic modifications that affect and alter the behavior of genes across the human genome.
The five-year, $16.6 million grant will support The San Diego Epigenome Center at the Ludwig Institute for Cancer Research at UC San Diego, one of four centers in the country called Reference Epigenome Mapping Centers (REMC) as part of an overall five-year, $190 million NIH program. Ren's grant will support interdisciplinary work to comprehensively map elements of the human epigenome, which Ren describes as "like an added dimension to the DNA string."
"The human epigenome is the next frontier of genomic research," said Ren. "Just as the Human Genome Project provided a picture of the sequence of genomes, our work will help create a map of the processes that impact gene regulation – what turns genes on and off – in order to improve our understanding of what drives human development and disease."
The epigenome plays a pivotal role in cellular differentiation, tissue formation and aging by regulating the transcriptional potential of the genome, specifying when and where genes are activated or expressed. Epigenetic processes, such as modifications to DNA-associated proteins called histones, control genetic activity by changing the three-dimensional structure of chromosomes. Diet and exposure to environmental chemicals throughout all stages of human development, among other factors, can cause such epigenetic changes that may turn on or turn off certain genes.
"Such modifications to the genetic blueprint may provide part of the answer to why some people are more susceptible to disease than others," Ren said. "Our hope is that understanding how and when epigenetic processes control genes throughout our lives will lead to more effective ways to prevent and treat disease."
He and colleagues will study aspects of epigenetics that drive differentiation in human embryonic cells (eHSC), including basic mechanisms that determine a cell's self-renewal or that cause these cells to differentiate along specific lineages, such as blood cells or neurons. As a comparison, they will also grow and collect human primary fibroblast cells, a major cell type found in skin and other connective tissue that is easily grown in cell culture.
"The differentiation of human embryonic stem cells involves selective activation or silencing of genes, a process controlled in part by the epigenetic state of the cell," said Ren. "The human embryonic stem cells provide a unique model system for investigating mechanisms of human development because they have an ability to replicate indefinitely while retaining the capacity to differentiate into an array of distinct cell types."
First, the researchers will generate global, genome-wide profiles of histone modifications. The "spool" around which DNA winds, histones are large families of proteins that regulate gene expression in complex ways – modifying genes at every point along the DNA.
The second element to be mapped is DNA methylation, a biochemical modification that has been linked to gene silencing. DNA methylation is essential for normal development and is associated with a number of key cellular processes including carcinogenesis.
"We will use reference maps of these two processes to examine how chromatin modifications and DNA methylation change during differentiation of pluripotent stems cells to different cell types," said Joseph Ecker, Ph.D., professor at the Salk Institute for Biological Studies in La Jolla, who will head the project to map cytosine methylation sites across the human genome. "By building comprehensive epigenome maps of stem cells, we can identify key genes that are epigenetically regulated. This will provide new and powerful tools, enabling scientists to develop novel therapies or diagnostic markers for cancer and other disease states."
Ecker's laboratory developed the high-throughput technology that will be use to map the state of DNA methylation in the nucleus of a cell. The researchers will integrate the data and visualization software from the project's major research groups into a standard informatics pipeline, allowing the gathering, analysis and distribution of large-scale epigenetic data that can then be shared with scientists around the world.
The following researchers will lead research groups in the San Diego Epigenome Center: Bing Ren (determining the histone modification status across the human genome); James Thomson, University of Wisconsin (growth and differentiation of human embryonic stem cells); Joseph Ecker, Salk Institute for Biological Studies (mapping cytosine methylation sites across the human genome); Michael Zang, Cold Spring Harbor Laboratory, (statistical and algorithmic support); and Wei Wang, UC San Diego Department of Chemistry (developing an informatics pipeline for collecting, storing, distributing and analyzing epigenome maps).