Martha L. Bulyk

Division of Genetics, Department of Medicine; Dept. of Pathology;
Harvard-MIT Division of Health Sciences & Technology (HST); Associate Member of The Broad Institute of MIT and Harvard
Harvard Medical School
New Research Building, Room 466d
77 Ave. Louis Pasteur
Boston, MA 02115
Tel: (617) 525-4725
Fax: (617) 525-4705
Email:mlbulyk@receptor.med.harvard.edu
Web Page: The Bulyk Lab Page
6 postdoctoral fellows, 2 graduate students, 2 lab technicians, 2 undergraduates

Although numerous eukaryotic genomes have been sequenced, much still remains to be understood about how the genes in those genomes are regulated. The interactions between transcription factors (TFs) and their DNA binding sites are an integral part of the regulatory networks within cells. We employ numerous combined experimental and computational strategies in studying these regulatory interactions, to discover cis regulatory codes in the genome.

To permit a genome-wide scan of all possible TF binding sites in a given genome, we have developed protein binding microarrays (PBMs), a DNA microarray-based technology that allows rapid, high-throughput characterization of the DNA binding site sequence specificities of proteins. We are examining essentially all known and predicted S. cerevisiae double-stranded DNA binding proteins in order to identify novel TFs, and to infer their condition-specific regulatory roles. We are using PBMs to study hundreds of TFs in Drosophila and mammals, so that we may predict sets of co-regulatory TFs acting together at candidate transcriptional cis regulatory modules, such as transcriptional enhancers. We are also examining the effects of protein-protein interactions in DNA binding, as well as the structural basis of protein-DNA binding specificity. We have developed computational strategies that employ comparative genomics methods for prediction of tissue-specific transcriptional enhancers in fly, and separately in human. Many of these predicted enhancers recently have been validated in vivo. In our analyses, we infer each TF’s relative importance for a given cell-type-specific gene expression pattern. We perform integrated analyses that combine DNA-protein interaction data with other types of genomic and proteomic data sets for deciphering transcriptional regulatory networks within cells.

The results of these experiments and analyses may permit a better understanding of the locations and organization of regulatory DNA elements, as well as their evolution. Future projects may examine other types of regulation, such as chromatin structure, the role of small molecule cofactors and post-translational modifications.

References (*co-1st authors; †co-corresponding authors):

• *Warner JB, *Philippakis AA, *Jaeger SA, He FS, Lin J, Bulyk ML. Systematic identification of mammalian regulatory motifs' target genes and functions. Nature Methods (2008) 5(4):347-53.
• *Zhu C, *Byers K, *McCord RM, Shi Z, Berger MF, Newburger D, Saulrieta K, Smith K, Shah M, Radhakrishnan M, Philippakis AA, Hu Y, De Masi F, Pacek M, Rolfs A, Murthy TVS, LaBaer J, Bulyk ML. High-resolution DNA binding specificity analysis of yeast transcription factors. Genome Research (2009) 19(4):556-66.
• *Badis G, *Berger MF, *Philippakis AA, *Talukder S, *Gehrke AR, *Jaeger SA, *Chan ET, Metzler G, Vedenko A, Chen X, Kuznetsov H, Wang C-F, Coburn D, Newburger D, Morris QD, †Hughes TR, †Bulyk ML. Diversity and complexity in DNA recognition by transcription factors. Science (2009) 324:1720-1723.
• *Grove C, *De Masi F, Alexa K, Newburger D, Alkema MJ, †Bulyk ML, †Walhout AJM. A multi-parameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell (2009) [in press]