Environmental Factor, May 2009, National Institute of Environmental Health Sciences
Birnbaumer To Lead NIH Director's Challenge Award Project
By Eddy Ball
On April 3, NIEHS Senior Investigator Lutz Birnbaumer, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/ln/ts/index.cfm), was notified that his ambitious project to better understand the mechanisms involved in epigenetic modifications was selected for support by the NIH Director's Challenge Award Program. One of eight such awards made this year, Birnbaumer's two-year project is a trans-NIH effort involving NIEHS Biostatistics Branch Principal Investigator Leping Li, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/bb/staff/li/index.cfm), and three senior investigators with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as collaborators - Ann Dean, Ph.D. (http://www2.niddk.nih.gov/NIDDKLabs/IntramuralFaculty/DeanAnn.htm) , Gary Felsenfeld, Ph.D. (http://www2.niddk.nih.gov/NIDDKLabs/IntramuralFaculty/FelsenfeldGary.htm) , and Karen Usdin, Ph.D. (http://www2.niddk.nih.gov/NIDDKLabs/IntramuralFaculty/UsdinKaren.htm)
The goal of the project, titled "The Methylome in Health and Disease: Survey of Unmethylated CpGs," is to define tissue- and cell-specific DNA methylation patterns that vary in health and disease. "Methylome" refers to the totality of DNA sites affected by methylation.
During normal development, the methylation of these dinucleotides - C and G linked by a phosphate group - triggers epigenetic alterations in gene expression that are involved in cell differentiation. Later in life, abnormal deposition and removal of methylation marks have been linked to a range of diseases such as cancer, obesity and metabolic syndrome.
According to Birnbaumer's proposal, the group has performed proof-of-principle experiments that lead them to believe they can be successful in mapping the methylome. Using methods developed in Birnbaumer's lab, the team prepared and sequenced chemical libraries of CpG tags derived from ends created by digestion of mouse liver DNA. The experiment returned 32 million sequences that mapped approximately one-third of the CpGs in the mouse genome back to unique sites. The researchers were able to map to 22,000 high-confidence unmethylated regions (HC UMRs) where CpGs are unmarked.
The team's proposal lists specific aims in regard to methodology, data collection and evaluation of outcome that promise to significantly advance research on the methylome. These advances include the following:
- Methodology - improving the tag recovery from DNA ends and automation used to map tags back to databases containing sequences of interest and developing a web-based mapping tool
- Data Collection - preparing CpG tag libraries from a variety of tissues, which will enable the team to test the hypothesis that HC UMRs vary from tissue to tissue
- Evaluation of Outcome - refining a high-resolution, digital approach for use in an unbiased, genome-wide search to map unmethylated CpGs back to single CpG sites
The NIH Director's Challenge Award will provide the project two years of support for personnel, equipment and supplies in FY 2009 and FY 2010, with second-year funding contingent upon review of the group's progress at the end of the first year of funding. At a mini-symposium in 2010, Birnbaumer and his colleagues will join the other awardees to present the results of their projects.