Regulation of GLI1 by cis DNA elements and epigenetic marks

Robert Taylor, Jun Long, Joon Won Yoon, Ronnie Childs, Kathrine B. Sylvestersen, Michael L. Nielsen, King Fu Leong, Stephen Iannaccone, David O. Walterhouse, David J Robbins, Philip Iannaccone

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

GLI1 is one of three transcription factors (GLI1, GLI2 and GLI3)that mediate the Hedgehog signal transduction pathway and play important roles in normal development. GLI1 and GLI2 form a positive-feedback loop and function as human oncogenes. The mouse and human GLI1 genes have untranslated 5′ exons and large introns 5′ of the translational start. Here we show that Sonic Hedgehog (SHH)stimulates occupancy in the introns by H3K27ac, H3K4me3 and the histone reader protein BRD4. H3K27ac and H3K4me3 occupancy is not significantly changed by removing BRD4 from the human intron and transcription start site (TSS)region. We identified six GLI binding sites (GBS)in the first intron of the human GLI1 gene that are in regions of high sequence conservation among mammals. GLI1 and GLI2 bind all of the GBS in vitro. Elimination of GBS1 and 4 attenuates transcriptional activation by GLI1. Elimination of GBS1, 2, and 4 attenuates transcriptional activation by GLI2. Eliminating all sites essentially eliminates reporter gene activation. Further, GLI1 binds the histone variant H2A.Z. These results suggest that GLI1 and GLI2 can regulate GLI1 expression through protein-protein interactions involving complexes of transcription factors, histone variants, and reader proteins in the regulatory intron of the GLI1 gene. GLI1 acting in trans on the GLI1 intron provides a mechanism for GLI1 positive feedback and auto-regulation. Understanding the combinatorial protein landscape in this locus will be important to interrupting the GLI positive feedback loop and providing new therapeutic approaches to cancers associated with GLI1 overexpression.

Original languageEnglish (US)
Pages (from-to)10-21
Number of pages12
JournalDNA Repair
Volume79
DOIs
StatePublished - Jul 1 2019

Fingerprint

Epigenomics
Introns
DNA
Genes
Histones
Transcriptional Activation
Hedgehogs
Chemical activation
Proteins
Feedback
Transcription Factors
Binding Sites
Signal transduction
Mammals
Transcription Initiation Site
Reporter Genes
Oncogenes
Exons
Signal Transduction
Conservation

Keywords

  • DNA-protein interaction
  • Epigenetics
  • Hedgehog signaling pathway
  • Oncogene
  • Transcription factor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Taylor, R., Long, J., Yoon, J. W., Childs, R., Sylvestersen, K. B., Nielsen, M. L., ... Iannaccone, P. (2019). Regulation of GLI1 by cis DNA elements and epigenetic marks. DNA Repair, 79, 10-21. https://doi.org/10.1016/j.dnarep.2019.04.011

Regulation of GLI1 by cis DNA elements and epigenetic marks. / Taylor, Robert; Long, Jun; Yoon, Joon Won; Childs, Ronnie; Sylvestersen, Kathrine B.; Nielsen, Michael L.; Leong, King Fu; Iannaccone, Stephen; Walterhouse, David O.; Robbins, David J; Iannaccone, Philip.

In: DNA Repair, Vol. 79, 01.07.2019, p. 10-21.

Research output: Contribution to journalArticle

Taylor, R, Long, J, Yoon, JW, Childs, R, Sylvestersen, KB, Nielsen, ML, Leong, KF, Iannaccone, S, Walterhouse, DO, Robbins, DJ & Iannaccone, P 2019, 'Regulation of GLI1 by cis DNA elements and epigenetic marks', DNA Repair, vol. 79, pp. 10-21. https://doi.org/10.1016/j.dnarep.2019.04.011
Taylor R, Long J, Yoon JW, Childs R, Sylvestersen KB, Nielsen ML et al. Regulation of GLI1 by cis DNA elements and epigenetic marks. DNA Repair. 2019 Jul 1;79:10-21. https://doi.org/10.1016/j.dnarep.2019.04.011
Taylor, Robert ; Long, Jun ; Yoon, Joon Won ; Childs, Ronnie ; Sylvestersen, Kathrine B. ; Nielsen, Michael L. ; Leong, King Fu ; Iannaccone, Stephen ; Walterhouse, David O. ; Robbins, David J ; Iannaccone, Philip. / Regulation of GLI1 by cis DNA elements and epigenetic marks. In: DNA Repair. 2019 ; Vol. 79. pp. 10-21.
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