Paul A. Wade, Ph.D.
Epigenetics & Stem Cell Biology Laboratory / Eukaryotic Transcriptional Regulation Group
Building 101, Room D416
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
DNA function is strongly influenced by the nucleoprotein structures of chromosomes. These organelles harbor the genetic code in the linear sequence of bases of the DNA polymer. Superimposed on DNA sequence is additional information contained in patterns of histone modification, DNA methylation, and local nucleoprotein architecture that constitute epigenetic information. This information is instructive to the enzymes dedicated to nuclear DNA physiology. A major challenge is to decipher the properties of epigenetic information. Knowledge gaps exist in the information content of the epigenome, the mechanisms utilized by cells to copy this information during cell division, and the identity and regulation of the machinery responsible for 'reading' the code. These issues are complicated by the biological certainty that, unlike the genetic code, the epigenetic code must be dynamic within an individual organism.
The long term goals of my laboratory are to understand gene regulation within the context of eukaryotic chromatin (popularly termed epigenetics), and to relate gene regulatory events (and the factors involved) to biological events in the cell. One approach we have taken is to study in detail a single chromatin regulator in an attempt to derive general principles that may apply to the larger family of such factors. For the past decade we have focused on the Mi-2/NuRD complex, a nuclear enzyme generally believed to function in the process of transcriptional repression. This complex has two independent enzymatic activities (chromatin remodeling ATPase and histone deacetylase) that are presumed integral to its biological functions. We have been studying gene regulatory events mediated by Mi-2/NuRD using two biological model systems ñ breast cancer and B lymphocyte development and differentiation. In both experimental models, we wish to address the following basic questions:
- What is the genomic distribution of Mi-2/NuRD complex and how is this controlled?
- What genes are regulated by Mi-2/NuRD complex - directly and indirectly?
- What mechanisms are utilized by Mi-2/NuRD complex to modulate gene activity?
- How does Mi-2/NuRD complex action influence biological properties of the relevant cell?
Historically, we have utilized candidate approaches to define target genes for in-depth study; we are currently developing genomic approaches to provide a deeper level of information.
As a complement to our studies on chromatin remodeling and histone modification, we have developed a second approach to investigate the relationship between epigenetic marks and DNA function. We have developed a microarray based system for analysis of DNA methylation patterns in mammalian cells and are currently using this system to study the process of lymphocyte activation as part of the normal immune response. Our results indicate that lymphocyte activation is accompanied by major alterations in global DNA methylation patterns. The mechanisms by which this process is regulated, the biological consequences, and the relationship to the environment are currently under investigation.
Dr. Wade obtained his Ph.D. degree from Indiana University and completed postdoctoral training with Alan Wolffe at NICHD. After 4 years as an assistant professor in the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, he moved to the NIH in 2004. Dr. Wade is currently a Senior Investigator in the Laboratory of Molecular Carcinogenesis where he heads the Eukaryotic Transcriptional Regulation group.
Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell. 2003;113(2):207-19.
Fujita N, Jaye DL, Geigerman C, Akyildiz A, Mooney MR, Boss JM, Wade PA. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell. 2004;119(1):75-86.
Lai AY, Mav D, Shah R, Grimm SA, Phadke D, Hatzi K, Melnick A, Geigerman C, Sobol SE, Jaye DL, Wade PA. DNA methylation profiling in human B cells reveals immune regulatory elements and epigenetic plasticity at Alu elements during B-cell activation. Genome Res. 2013;23(12):2030-41.
Lai AY, Fatemi M, Dhasarathy A, Malone C, Sobol SE, Geigerman C, Jaye DL, Mav D, Shah R, Li L, Wade PA. DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas. J Exp Med. 2010;207(9):1939-50.
Li R, Grimm SA, Chrysovergis K, Kosak J, Wang X, Du Y, Burkholder A, Janardhan K, Mav D, Shah R, Eling TE, Wade PA. Obesity, rather than diet, drives epigenomic alterations in colonic epithelium resembling cancer progression. Cell Metab. 2014;19(4):702-11.