Chromatin properties of regulatory DNA probed by manipulation of transcription factors

Alexei A. Sharov, Akira Nishiyama, Yong Qian, Dawood B. Dudekula, Dan L. Longo, David Schlessinger, Minoru S.H. Ko

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Transcription factors (TFs) bind to DNA and regulate the transcription of nearby genes. However, only a small fraction of TF binding sites have such regulatory effects. Here we search for the predictors of functional binding sites by carrying out a systematic computational screening of a variety of contextual factors (histone modifications, nuclear lamin-bindings, and cofactor bindings). We used regression analysis to test if contextual factors are associated with upregulation or downregulation of neighboring genes following the induction or knockdown of the 9 TFs in mouse embryonic stem (ES) cells. Functional TF binding sites appeared to be either active (i.e., bound by P300, CHD7, mediator, cohesin, and SWI/SNF) or repressed (i.e., with H3K27me3 histone marks and bound by Polycomb factors). Active binding sites mediated the downregulation of nearby genes upon knocking down the activating TFs or inducing repressors. Repressed TF binding sites mediated the upregulation of nearby genes (e.g., poised developmental regulators) upon inducing TFs. In addition, repressed binding sites mediated repressive effects of TFs, identified by the downregulation of target genes after the induction of TFs or by the upregulation of target genes after the knockdown of TFs. The contextual factors associated with functions of DNA-bound TFs were used to improve the identification of candidate target genes regulated by TFs.

Original languageEnglish
Pages (from-to)569-577
Number of pages9
JournalJournal of Computational Biology
Volume21
Issue number8
DOIs
Publication statusPublished - 2014 Aug 1

Keywords

  • chromatin modification
  • cis-regulatory module
  • embryonic stem cells
  • enhancer
  • target genes
  • transcription factor binding site

ASJC Scopus subject areas

  • Modelling and Simulation
  • Molecular Biology
  • Genetics
  • Computational Mathematics
  • Computational Theory and Mathematics

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  • Cite this

    Sharov, A. A., Nishiyama, A., Qian, Y., Dudekula, D. B., Longo, D. L., Schlessinger, D., & Ko, M. S. H. (2014). Chromatin properties of regulatory DNA probed by manipulation of transcription factors. Journal of Computational Biology, 21(8), 569-577. https://doi.org/10.1089/cmb.2013.0126