Regulation of GLI1 by cis DNA elements and epigenetic marks

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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, 2019, p. 10-21.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Taylor, R, Long, J, Yoon, JW, Childs, R, Sylvestersen, KB, Nielsen, ML, Leong, K-F, 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

APA

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

Vancouver

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;79:10-21. https://doi.org/10.1016/j.dnarep.2019.04.011

Author

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.

Bibtex

@article{67384931e51647b49295fa19ce6b60cc,
title = "Regulation of GLI1 by cis DNA elements and epigenetic marks",
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.",
author = "Robert Taylor and Jun Long and Yoon, {Joon Won} and Ronnie Childs and Sylvestersen, {Kathrine B.} and Nielsen, {Michael L.} and King-Fu Leong and Stephen Iannaccone and Walterhouse, {David O} and Robbins, {David J} and Philip Iannaccone",
year = "2019",
doi = "10.1016/j.dnarep.2019.04.011",
language = "English",
volume = "79",
pages = "10--21",
journal = "D N A Repair",
issn = "1568-7864",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Regulation of GLI1 by cis DNA elements and epigenetic marks

AU - Taylor, Robert

AU - Long, Jun

AU - Yoon, Joon Won

AU - Childs, Ronnie

AU - Sylvestersen, Kathrine B.

AU - Nielsen, Michael L.

AU - Leong, King-Fu

AU - Iannaccone, Stephen

AU - Walterhouse, David O

AU - Robbins, David J

AU - Iannaccone, Philip

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1016/j.dnarep.2019.04.011

DO - 10.1016/j.dnarep.2019.04.011

M3 - Journal article

C2 - 31085420

VL - 79

SP - 10

EP - 21

JO - D N A Repair

JF - D N A Repair

SN - 1568-7864

ER -

ID: 219532685