Research Interests:

We study various aspects of DNA-protein interactions, with the development and use of genomic and proteomic technologies and computational approaches. Although many organisms’ genomes have been sequenced, allowing for comparative sequence analysis, much still remains to be understood about how those genes are regulated. The interactions between transcription factors and their DNA binding sites are an integral part of the regulatory networks within cells. Data on the binding of transcription factors to their DNA sites, combined with data from other genomic, proteomic, and computational approaches, will permit a more complete delineation of the interplay of various regulatory pathways.

To address the lack of high-resolution DNA binding specificity data for the large majority of known and predicted transcription factors, we have developed a microarray technology that permits measurement of the direct binding of transcription factors to DNA microarrays. This protein binding microarray (PBM) technology allows us to identify candidate genomic locations of transcription factor binding sites. It also allows us to distinguish the DNA binding preferences of highly homologous proteins. Comparison of PBM-derived DNA binding sites versus their in vivo binding sites indicates that PBM-derived sequence specificities can accurately reflect in vivo DNA sequence specificities. Comparative sequence analysis indicates that many of these newly identified, PBM-derived sites are highly conserved and thus are likely to be functional in vivo binding sites that potentially are utilized in a condition-specific manner. We use PBM-derived DNA binding profiles in combination with other genomic and proteomic data types to identify cis regulatory elements and transcriptional regulatory interactions in various organisms (yeast, C. elegans, fly, mammals).

We are also working on elucidating transcriptional regulatory networks in these organisms. In metazoan genomes, regulatory elements can be found far upstream of promoters, as well as in introns or downstream of the genes they regulate. We have used computational approaches to successfully predict transcriptional enhancers in fly and in human. We are continuing to develop improved computational methods for the analysis and prediction of functional regulatory elements, in order to better understand the transcriptional regulation afforded by combinations of transcription factors, and to better understand the organization of regulatory DNA elements.

Ongoing projects in the lab include: inference of cis regulatory codes associated with spatiotemporal gene expression patterns in fly or mammals; identifying and understanding chromosomal interactions involving regulatory elements in mammalian genomes; analysis of how transcription factor DNA binding site affinities pertain to their gene regulatory roles; evolution of transcription factors and genomic regulatory elements; analysis of how various structural aspects of transcription factors affect their DNA binding affinities; identification of novel classes of DNA binding domains; exploring the effects of post-translational modifications and DNA methylation on transcription factors’ DNA binding preferences; examination of the regulatory roles of newly identified transcription factors, in a wide range of organisms; integration of protein-protein interaction data, gene expression data, and DNA binding specificity data to understand how gene regulatory specificity is achieved by different members of a given transcription factor family.

Selected Publications:

*Berger, M.F., *Badis, G., *Gehrke, A.R., *Talukder, S., Philippakis, A.A., Peña-Castillo, L., Alleyne, T.M., Mnaimneh, S., Botvinnik, O.B., Chan, E.T., Khalid, F., Zhang, W., Newburger, D., Jaeger, S.A., Morris, Q.D., †Bulyk, M.L., †Hughes, T.R. (2008) Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 133: 1266-1276. (*co-1st authors; †co-corresponding authors).

*Warner, J.B., *Philippakis, A.A., *Jaeger, S.A., He, F.S., Lin, J., Bulyk, M.L. (2008) Systematic identification of mammalian regulatory motifs' target genes and functions. Nature Methods 5(4): 347-53. Epub 2008 Mar 2 (* co-1st authors).

McCord, R.P. and Bulyk, M.L. (2008) Functional trends in structural classes of the DNA binding domains of regulatory transcription factors. Pacific Symposium on Biocomputing 13: 441-452.

McCord, R.P., Berger, M.F., Philippakis, A.A., Bulyk, M.L. (2007) Inferring condition-specific transcription factor function from DNA binding and gene expression. Molecular Systems Biology 3: 100.