David C. Williams, Jr.

M.D., Ph.D., Department of Pathology and Laboratory Medicine, UNC-Chapel Hill, Molecular Therapeutics

David C. Williams, Jr.

M.D., Ph.D.
Department of Pathology and Laboratory Medicine
UNC-Chapel Hill
Molecular Therapeutics

909 Brinkhous Bullitt
919-843-9949

Laboratory Website
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Area of interest

My laboratory uses structural and biophysical techniques to probe protein-protein and protein-DNA interactions critical to the formation of macromolecular complexes.   Over the past several years, we have been studying the Nucleosome Remodeling and Deacetylase (NuRD) complex responsible for recognizing methylated DNA and silencing expression of the associated genes.  Our focus has been to understand how a key component of this complex, the methyl-cytosine binding domain protein 2 (MBD2), binds DNA and recruits the rest of NuRD.

DNA methylation represents a key epigenetic signal involved in both normal developmental silencing of genes as well as aberrant silencing of tumor suppressor genes in cancer.  The methylation mark is recognized by a family of proteins that contain a ~60 amino acid methyl-cytosine binding domain (MBD) including MeCP2 and MBD1-4.  The primary focus of our studies, MBD2, binds methylated promoters and recruits at least five proteins (p66α/β, MTA2, RbAp46/48, HDAC1/2, and Mi2α/β) that alter the chromatin structure and silence transcription of the associated gene. The structural and biophysical details of any of the specific intermolecular interactions forming MBD2-NuRD are an active area of investigation.   We recently determined the structure of the coiled-coil complex formed between MBD2 and the p66a protein and showed that disrupting this interaction restores expression of methylated genes.1  Since knockout of MBD2 in mice leads to only mild phenotypic consequences, inhibition of MBD2 represents a potential biological target to restore expression of tumor suppressor genes silenced by DNA methylation.  Importantly, work by our collaborators and others have shown that disrupting the function of MBD2 can block tumor cell growth in tissue culture and in vivo.

Currently we are studying different domains of MBD2 using structural analyses by NMR complimented by a variety of biophysical techniques.  The N-terminal methyl-cytosine binding domain adopts a well-folded structure once bound to DNA but shows evidence of rapid translocation between methylated sites.  We are comparing DNA binding and dynamics between different members of the MBD family to better understand functional differences.   In contrast, the coiled-coil domain in MBD2 forms a very stable and high affinity interaction with p66a of NuRD.  We are characterizing the minimal requirements for high affinity coiled-coil complex formation with the goal of developing a method to inhibit this interaction.   Finally, we are studying a largely unstructured region from MBD2, which is necessary and sufficient for binding and recruiting other components of the NuRD complex.  Ultimately the goal of these studies is to understand the structural mechanism of methylation dependent gene silencing by MBD2 and to develop inhibitors of complex formation for therapeutic benefit.

1. Gnanapragasam, M. N. et al. p66{alpha}-MBD2 coiled-coil interaction and recruitment of Mi-2 are critical for globin gene silencing by the MBD2-NuRD complex. Proc. Natl. Acad. Sci. U. S. A. 108, 7487-7492 (2011).

Awards and Honors

1989 Phi Beta Kappa member elect
1990 Graduated with Highest Honors, College of William and Mary
1992 Alpha Omega Alpha national medical honor society
1996 Keystone Award for Outstanding Scientific Contribution, Keystone Symposium
1997 Invited Speaker to the Mid-Atlantic Immunobiology Conference, “Amide
hydrogen exchange rates in an Fv fragment free and bound to antibody”
1990-1998 Medical Scientist Training Program, University of Virginia, Charlottesville, VA
2001-2004 PRAT Fellowship, National Institute of General Medical Sciences, Bethesda, MD

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