The primary focus of our research is to utilize a multidisciplinary approach incorporating structural biology, biophysics, biochemistry, molecular biology and cellular biology to investigate mechanistic questions in the area of transcriptional regulation. We are particularly interested in applying these methodologies to discern structure-function relationships for specialized transcription factors that recognize epigenetically modified methyl-CpG DNA sequences.
In eukaryotes, DNA methylation in the context of CpG dinucleotides is an essential epigenetic modification required for genomic stability, regulation of chromatin structure and long-term transcriptional silencing of genes. It is becoming increasingly evident that nearly all cancers exhibit aberrant alterations in DNA methylation preceding tumorigenesis. DNA methylation leads to alterations in gene transcription through two primary mechanisms: abrogating the ability of transcription factors to localize to their consensus sites or recruitment of specialized transcription factors that selectively recognize mCpG targets. These designated methyl-CpG binding proteins (MBPs) then promote recruitment of enzyme complexes that remodel chromatin and alter transcription. Thus, MBPs represent the functional intermediaries between reading DNA methylation and translating these epigenetic signals into a down-stream transcriptional response. However, detailed mechanistic insight for how MBPs globally mediate this essential cellular process remains to be elucidated.
Active areas of research in our laboratory include: 1) Utilizing a parallel in vitro biophysical/structural and in cell genomic approach to delineate the molecular mechanisms by which these proteins recognize their cognate DNA targets and regulate transcription in the cancerous state; 2) structural characterization of these MBP:DNA interactions to ascertain modes of mCpG recognition for various MBPs; and 3) structural and biophysical characterizations of protein/protein interactions to begin evaluating how interpretation of the methylation signal triggers chromatin remodeling. Structure-function evaluation of MBPs with their interaction partners is critical for gaining mechanistic insight into the complex roles of these proteins in cancer epigenetics. It is anticipated that long-term this research will establish the basis for advancing therapeutic design directed toward key MBP regulatory networks/pathways.