Martha Bulyk, Ph.D.
Professor of Medicine and Pathology
Brigham & Women’s Hospital and Harvard Medical School

“Transcription factor – DNA interactions: unraveling new twists in molecular recognition, genetic variation, and gene regulation”

The interactions between transcription factor (TFs) and their DNA binding sites are an integral part of the gene regulatory networks within cells. Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human TFs. In surveying TF variant alleles found in individuals of diverse ancestries and families with Mendelian diseases, we have found variants that affect DNA-binding affinity or specificity and have identified thousands of rare alleles likely to alter their DNA-binding activity. Our results suggest that most individuals have unique repertoires of TF DNA-binding activities. Accurate prediction of the effects of mutations on TF DNA binding requires understanding of the determinants of TF-DNA binding activity. Analysis of forkhead class of TFs has revealed the evolution of recognition of an alternate motif that is strikingly different from the canonical forkhead motif; surprisingly, some forkhead TFs are bispecific, recognizing two very different motifs. Our recent structural and biochemical studies of forkhead TFs have revealed the basis for such bispecificity. Understanding how gene regulatory patterns are specified also requires an understanding of cis-regulatory elements. While transcriptional enhancers have been studied extensively, few transcriptional silencers have been identified and they remain poorly understood. In recent work, we have identified tissue-specific silencers in Drosophila embryos, assayed their regulatory activities, examined their genomic features and chromosomal interactions, and suggest models for how they may exert their regulatory effects.

Reading Material:

1. Luis A. Barrera, Anastasia Vedenko, Martha L. Bulyk, et al. Survey of variation in human transcription factors reveals prevalent DNA binding changes. Sciencemag.org Vol 351, Issue 6280 (25 March 2016)
2. Julia M. Rogers, Colin T. Waters, Martha L. Bulyk, et al. Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes. Molecular Cell 74, 1–9, April 18, 201
3. Rogers JM, Bulyk ML. Diversification of transcription factor–DNA interactions and the evolution of gene regulatory networks. WIREs Syst Biol Med. 2018;e1423

(Faculty host: James Ferrell)