Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding.

Journal Article (Journal Article)

Paralogous transcription factors (TFs) are oftentimes reported to have identical DNA-binding motifs, despite the fact that they perform distinct regulatory functions. Differential genomic targeting by paralogous TFs is generally assumed to be due to interactions with protein co-factors or the chromatin environment. Using a computational-experimental framework called iMADS (integrative modeling and analysis of differential specificity), we show that, contrary to previous assumptions, paralogous TFs bind differently to genomic target sites even in vitro. We used iMADS to quantify, model, and analyze specificity differences between 11 TFs from 4 protein families. We found that paralogous TFs have diverged mainly at medium- and low-affinity sites, which are poorly captured by current motif models. We identify sequence and shape features differentially preferred by paralogous TFs, and we show that the intrinsic differences in specificity among paralogous TFs contribute to their differential in vivo binding. Thus, our study represents a step forward in deciphering the molecular mechanisms of differential specificity in TF families.

Full Text

Duke Authors

Cited Authors

  • Shen, N; Zhao, J; Schipper, JL; Zhang, Y; Bepler, T; Leehr, D; Bradley, J; Horton, J; Lapp, H; Gordan, R

Published Date

  • April 25, 2018

Published In

Volume / Issue

  • 6 / 4

Start / End Page

  • 470 - 483.e8

PubMed ID

  • 29605182

Pubmed Central ID

  • PMC6008103

International Standard Serial Number (ISSN)

  • 2405-4712

Digital Object Identifier (DOI)

  • 10.1016/j.cels.2018.02.009


  • eng

Conference Location

  • United States