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Regulation of GLI1 by cis DNA elements and epigenetic marks
- Source :
- Taylor, R, Long, J, Yoon, J W, Childs, R, Sylvestersen, K B, Nielsen, M L, Leong, K-F, Iannaccone, S, Walterhouse, D O, Robbins, D J & 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, DNA repair
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
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.
- Subjects :
- Transcriptional Activation
Hedgehog signaling pathway
animal structures
Cell Cycle Proteins
Zinc Finger Protein GLI1
Biochemistry
Article
Cell Line
Epigenesis, Genetic
Histones
Mice
03 medical and health sciences
0302 clinical medicine
Animals
Humans
Hedgehog Proteins
Protein–DNA interaction
Sonic hedgehog
Molecular Biology
Gene
Transcription factor
Cells, Cultured
Oncogene
030304 developmental biology
Feedback, Physiological
0303 health sciences
Binding Sites
integumentary system
biology
DNA-protein interaction
Intron
Epigenetic
Cell Biology
Cell biology
Enhancer Elements, Genetic
Histone
030220 oncology & carcinogenesis
biology.protein
H3K4me3
Protein Binding
Transcription Factors
Subjects
Details
- ISSN :
- 15687864
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- DNA Repair
- Accession number :
- edsair.doi.dedup.....e5f513f01ed19892e9a068d8432c2d4d
- Full Text :
- https://doi.org/10.1016/j.dnarep.2019.04.011