Photo of Martha L. Bulyk,   PhD

Martha L. Bulyk, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-4725

Martha L. Bulyk, PhD

Brigham And Women's Hospital


  • Professor, Medicine, Harvard Medical School
  • Professor, Pathology, Harvard Medical School
  • Professor, Div. Genetics, Dept. Medicine, Brigham And Women's Hospital
  • Associate Professor, Department of Pathology, Brigham And Women's Hospital
  • Principal Investigator, Bulyk Laboratory, Brigham And Women's Hospital


Research Abstract

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 developed universal 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 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 examining the effects of protein-protein interactions in DNA binding. We are also investigating divergence within TF families and how different members of a TF family gain distinct regulatory roles. We are investigating the effects of mutations and naturally occurring genetic variation on human TFs. We are combining sequence, evolutionary, structural, and PBM data to understand the molecular determinants of protein-DNA binding specificity and its evolution. We have developed computational strategies that employ comparative genomics methods for prediction of tissue-specific transcriptional enhancers in fly, and separately in mammals. 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 are interested in understanding the quantitative nature of information encoded within transcriptional enhancers, as it pertains to spatiotemporal specificity of enhancer activity. Technology development projects include novel approaches for high-throughput, experimental identification of tissue/cell-type-specific enhancers. The results of these experiments and analyses aim for a better understanding of the functions, locations and organization of DNA regulatory elements, and their evolution.


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  • Menke C, Cionni M, Siggers T, Bulyk ML, Beier DR, Stottmann RW. Grhl2 is required in non-neural tissues for neural progenitor survival and forebrain development. Genesis 2015. PubMed
  • Satterstrom FK, Swindell WR, Laurent G, Vyas S, Bulyk ML, Haigis MC. Nuclear respiratory factor 2 induces SIRT3 expression. Aging Cell 2015. PubMed
  • Hume MA, Barrera LA, Gisselbrecht SS, Bulyk ML. UniPROBE, update 2015: new tools and content for the online database of protein-binding microarray data on protein-DNA interactions. Nucleic Acids Res 2015; 43:D117-22. PubMed
  • Rogers JM, Barrera LA, Reyon D, Sander JD, Kellis M, Joung JK, Bulyk ML. Context influences on TALE-DNA binding revealed by quantitative profiling. Nat Commun 2015; 6:7440. PubMed
  • Cheatle Jarvela AM, Brubaker L, Vedenko A, Gupta A, Armitage BA, Bulyk ML, Hinman VF. Modular Evolution of DNA-Binding Preference of a Tbrain Transcription Factor Provides a Mechanism for Modifying Gene Regulatory Networks. Mol. Biol. Evol. 2014; 31:2672-88. PubMed
  • Zhao B, Barrera LA, Ersing I, Willox B, Schmidt SC, Greenfeld H, Zhou H, Mollo SB, Shi TT, Takasaki K, Jiang S, Cahir-McFarland E, Kellis M, Bulyk ML, Kieff E, Gewurz BE. The NF-虜B Genomic Landscape in Lymphoblastoid B Cells. Cell Rep 2014; 8:1595-606. PubMed
  • Siggers T, Reddy J, Barron B, Bulyk ML. Diversification of transcription factor paralogs via noncanonical modularity in C2H2 zinc finger DNA binding. Mol Cell 2014; 55:640-8. PubMed
  • Ahmad SM, Busser BW, Huang D, Cozart EJ, Michaud S, Zhu X, Jeffries N, Aboukhalil A, Bulyk ML, Ovcharenko I, Michelson AM. Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification. Development 2014; 141:878-88. PubMed
  • Gisselbrecht SS, Barrera LA, Porsch M, Aboukhalil A, Estep PW, Vedenko A, Palagi A, Kim Y, Zhu X, Busser BW, Gamble CE, Iagovitina A, Singhania A, Michelson AM, Bulyk ML. Highly parallel assays of tissue-specific enhancers in whole Drosophila embryos. Nat Methods 2013; 10:774-80. PubMed
  • Nakagawa S, Gisselbrecht SS, Rogers JM, Hartl DL, Bulyk ML. DNA-binding specificity changes in the evolution of forkhead transcription factors. Proc Natl Acad Sci U S A 2013; 110:12349-54. PubMed
  • Soruco MM, Chery J, Bishop EP, Siggers T, Tolstorukov MY, Leydon AR, Sugden AU, Goebel K, Feng J, Xia P, Vedenko A, Bulyk ML, Park PJ, Larschan E. The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation. Genes Dev 2013; 27:1551-6. PubMed
  • Jiang B, Liu JS, Bulyk ML. Bayesian hierarchical model of protein binding microarray k-mer data reduces noise and identifies transcription factor subclasses and preferred k-mers. Bioinformatics 2013. PubMed
  • Gordân R, Shen N, Dror I, Zhou T, Horton J, Rohs R, Bulyk ML. Genomic Regions Flanking E-Box Binding Sites Influence DNA Binding Specificity of bHLH Transcription Factors through DNA Shape. Cell Rep 2013. PubMed
  • Weirauch MT, Cote A, Norel R, Annala M, Zhao Y, Riley TR, Saez-Rodriguez J, Cokelaer T, Vedenko A, Talukder S, , Bussemaker HJ, Morris QD, Bulyk ML, Stolovitzky G, Hughes TR. Evaluation of methods for modeling transcription factor sequence specificity. Nat Biotechnol 2013; 31:126-34. PubMed
  • Busser BW, Gisselbrecht SS, Shokri L, Tansey TR, Gamble CE, Bulyk ML, Michelson AM. Contribution of distinct homeodomain DNA binding specificities to Drosophila embryonic mesodermal cell-specific gene expression programs. PLoS ONE 2013; 8:e69385. PubMed
  • Busser BW, Huang D, Rogacki KR, Lane EA, Shokri L, Ni T, Gamble CE, Gisselbrecht SS, Zhu J, Bulyk ML, Ovcharenko I, Michelson AM. Integrative analysis of the zinc finger transcription factor Lame duck in the Drosophila myogenic gene regulatory network. Proc Natl Acad Sci U S A 2012; 109:20768-73. PubMed
  • Charoensawan V, Janga SC, Bulyk ML, Babu MM, Teichmann SA. DNA sequence preferences of transcriptional activators correlate more strongly than repressors with nucleosomes. Mol Cell 2012; 47:183-92. PubMed
  • De Masi F, Grove CA, Vedenko A, Alibés A, Gisselbrecht SS, Serrano L, Bulyk ML, Walhout AJ. Using a structural and logics systems approach to infer bHLH-DNA binding specificity determinants. Nucleic Acids Res 2011. PubMed
  • Helfer A, Nusinow DA, Chow BY, Gehrke AR, Bulyk ML, Kay SA. LUX ARRHYTHMO encodes a nighttime repressor of circadian gene expression in the Arabidopsis core clock. Curr Biol 2011; 21:126-33. PubMed
  • Robasky K, Bulyk ML. UniPROBE, update 2011: expanded content and search tools in the online database of protein-binding microarray data on protein-DNA interactions. Nucleic Acids Res 2010; 39:D124-8. PubMed
  • Santos MA, Turinsky AL, Ong S, Tsai J, Berger MF, Badis G, Talukder S, Gehrke AR, Bulyk ML, Hughes TR, Wodak SJ. Objective sequence-based subfamily classifications of mouse homeodomains reflect their in vitro DNA-binding preferences. Nucleic Acids Res 2010; 38:7927-42. PubMed
  • Alibés A, Nadra AD, De Masi F, Bulyk ML, Serrano L, Stricher F. Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: the Pax6 example. Nucleic Acids Res 2010; 38:7422-31. PubMed
  • Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 2010; 39:493-506. PubMed
  • Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M, Bonke M, Jolma A, Varjosalo M, Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes TR, Bulyk ML, Taipale J. Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 2010; 29:2147-60. PubMed
  • Rowan S, Siggers T, Lachke SA, Yue Y, Bulyk ML, Maas RL. Precise temporal control of the eye regulatory gene Pax6 via enhancer-binding site affinity. Genes Dev 2010; 24:980-5. PubMed
  • Hirsch HA, Iliopoulos D, Joshi A, Zhang Y, Jaeger SA, Bulyk M, Tsichlis PN, Shirley Liu X, Struhl K. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 2010; 17:348-61. PubMed
  • Jaeger SA, Chan ET, Berger MF, Stottmann R, Hughes TR, Bulyk ML. Conservation and regulatory associations of a wide affinity range of mouse transcription factor binding sites. Genomics 2010; 95:185-95. PubMed
  • Giorgetti L, Siggers T, Tiana G, Caprara G, Notarbartolo S, Corona T, Pasparakis M, Milani P, Bulyk ML, Natoli G. Noncooperative interactions between transcription factors and clustered DNA binding sites enable graded transcriptional responses to environmental inputs. Mol Cell 2010; 37:418-28. PubMed
  • Enriquez J, Boukhatmi H, Dubois L, Philippakis AA, Bulyk ML, Michelson AM, Crozatier M, Vincent A. Multi-step control of muscle diversity by Hox proteins in the Drosophila embryo. Development 2010; 137:457-66. PubMed
  • Del Bianco C, Vedenko A, Choi SH, Berger MF, Shokri L, Bulyk ML, Blacklow SC. Notch and MAML-1 complexation do not detectably alter the dna binding specificity of the transcription factor CSL. PLoS ONE 2010; 5:e15034. PubMed
  • Bulyk ML, Levine M. Genomes and evolution: advances in deciphering the genomics of gene regulation in evolution. Curr Opin Genet Dev 2009; 19:533-4. PubMed
  • Gordân R, Hartemink AJ, Bulyk ML. Distinguishing direct versus indirect transcription factor-DNA interactions. Genome Res 2009; 19:2090-100. PubMed
  • Grove CA, De Masi F, Barrasa MI, Newburger DE, Alkema MJ, Bulyk ML, Walhout AJ. A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors. Cell 2009; 138:314-27. PubMed
  • Badis G,Berger MF,Philippakis AA,Talukder S,Gehrke AR,Jaeger SA,Chan ET,Metzler G,Vedenko A,Chen X,Kuznetsov H,Wang CF,Coburn D,Newburger DE,Morris Q,Hughes TR,Bulyk ML. Diversity and Complexity in DNA Recognition by Transcription Factors. Science 2009; 324:1720-3. PubMed
  • Alleyne TM,Pena-Castillo L,Badis G,Talukder S,Berger MF,Gehrke AR,Philippakis AA,Bulyk ML,Morris QD,Hughes TR. Predicting the binding preference of transcription factors to individual DNA k-mers. Bioinformatics 2008; 25:1012-8. PubMed
  • Lesch BJ,Gehrke AR,Bulyk ML,Bargmann CI. Transcriptional regulation and stabilization of left-right neuronal identity in C. elegans. Genes Dev 2009; 23:345-58. PubMed
  • Scharer CD,McCabe CD,Ali-Seyed M,Berger MF,Bulyk ML,Moreno CS. Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. Cancer Res 2009; 69:709-17. PubMed
  • Newburger DE,Bulyk ML. UniPROBE: an online database of protein binding microarray data on protein-DNA interactions. Nucleic Acids Res 2008; 37:D77-82. PubMed
  • Berger MF,Bulyk ML. Universal protein-binding microarrays for the comprehensive characterization of the DNA-binding specificities of transcription factors. Nat Protoc 2009; 4:393-411. PubMed
  • Viiri KM,Janis J,Siggers T,Heinonen TY,Valjakka J,Bulyk ML,Maki M,Lohi O. DNA-binding and -bending activities of SAP30L and SAP30 are mediated by a zinc-dependent module and monophosphoinositides. Mol Cell Biol 2008; 29:342-56. PubMed
  • Estep PW 3rd,Warner JB,Bulyk ML. Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS ONE 2009; 4:e5242. PubMed
  • Busser BW,Bulyk ML,Michelson AM. Toward a systems-level understanding of developmental regulatory networks. Curr Opin Genet Dev 2008; 18:521-9. PubMed
  • Pompeani AJ,Irgon JJ,Berger MF,Bulyk ML,Wingreen NS,Bassler BL. The Vibrio harveyi master quorum-sensing regulator, LuxR, a TetR-type protein is both an activator and a repressor: DNA recognition and binding specificity at target promoters. Mol Microbiol 2008; 70:76-88. PubMed
  • Philippakis AA,Qureshi AM,Berger MF,Bulyk ML. Design of compact, universal DNA microarrays for protein binding microarray experiments. J Comput Biol 2008; 15:655-65. PubMed
  • Berger MF,Badis G,Gehrke AR,Talukder S,Philippakis AA,Pena-Castillo L,Alleyne TM,Mnaimneh S,Botvinnik OB,Chan ET,Khalid F,Zhang W,Newburger D,Jaeger SA,Morris QD,Bulyk ML,Hughes TR. Variation in homeodomain DNA binding revealed by high-resolution analysis of sequence preferences. Cell 2008; 133:1266-76. PubMed
  • De Silva EK,Gehrke AR,Olszewski K,Leon I,Chahal JS,Bulyk ML,Llinas M. Specific DNA-binding by apicomplexan AP2 transcription factors. Proc Natl Acad Sci U S A 2008; 105:8393-8. PubMed
  • Warner JB, Philippakis AA, Jaeger SA, He FS, Lin J, Bulyk ML. Systematic identification of mammalian regulatory motifs' target genes and functions. Nat Methods 2008; 5:347-53. PubMed
  • McCord RP, Bulyk ML. Functional trends in structural classes of the DNA binding domains of regulatory transcription factors. Pac Symp Biocomput 2008. PubMed
  • Lieb JD, Beck S, Bulyk ML, Farnham P, Hattori N, Henikoff S, Liu XS, Okumura K, Shiota K, Ushijima T, Greally JM. Applying whole-genome studies of epigenetic regulation to study human disease. Cytogenet Genome Res 2006; 114:1-15. PubMed