Dual roles of c-Myc in the regulation of hTERT gene
Human telomerase gene hTERT is important for cancer and aging. hTERT promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment. However, it remains unsolved how the interplay between TFs and chromatin environment controls hTERT transcrip...
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Oxford University Press
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176324/ |
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pubmed-41763242014-12-01 Dual roles of c-Myc in the regulation of hTERT gene Zhao, Yuanjun Cheng, De Wang, Shuwen Zhu, Jiyue Gene regulation, Chromatin and Epigenetics Human telomerase gene hTERT is important for cancer and aging. hTERT promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment. However, it remains unsolved how the interplay between TFs and chromatin environment controls hTERT transcription. In this study, we employed the recombinase-mediated BAC targeting and BAC recombineering techniques to dissect the functions of two proximal E-box sites at −165 and +44 nt in regulating the hTERT promoter in the native genomic contexts. Our data showed that mutations of these sites abolished promoter binding by c-Myc/Max, USF1 and USF2, decreased hTERT promoter activity, and prevented its activation by overexpressed c-Myc. Upon inhibition of histone deacetylases, mutant and wildtype promoters were induced to the same level, indicating that the E-boxes functioned to de-repress the hTERT promoter and allowed its transcription in a repressive chromatin environment. Unexpectedly, knockdown of endogenous c-Myc/Max proteins activated hTERT promoter. This activation did not require the proximal E-boxes but was accompanied by increased promoter accessibility, as indicated by augmented active histone marks and binding of multiple TFs at the promoter. Our studies demonstrated that c-Myc/Max functioned in maintaining chromatin-dependent repression of the hTERT gene in addition to activating its promoter. Oxford University Press 2014-09-15 2014-08-28 /pmc/articles/PMC4176324/ /pubmed/25170084 http://dx.doi.org/10.1093/nar/gku721 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Zhao, Yuanjun Cheng, De Wang, Shuwen Zhu, Jiyue |
| spellingShingle |
Zhao, Yuanjun Cheng, De Wang, Shuwen Zhu, Jiyue Dual roles of c-Myc in the regulation of hTERT gene |
| author_facet |
Zhao, Yuanjun Cheng, De Wang, Shuwen Zhu, Jiyue |
| author_sort |
Zhao, Yuanjun |
| title |
Dual roles of c-Myc in the regulation of hTERT gene |
| title_short |
Dual roles of c-Myc in the regulation of hTERT gene |
| title_full |
Dual roles of c-Myc in the regulation of hTERT gene |
| title_fullStr |
Dual roles of c-Myc in the regulation of hTERT gene |
| title_full_unstemmed |
Dual roles of c-Myc in the regulation of hTERT gene |
| title_sort |
dual roles of c-myc in the regulation of htert gene |
| description |
Human telomerase gene hTERT is important for cancer and aging. hTERT promoter is regulated by multiple transcription factors (TFs) and its activity is dependent on the chromatin environment. However, it remains unsolved how the interplay between TFs and chromatin environment controls hTERT transcription. In this study, we employed the recombinase-mediated BAC targeting and BAC recombineering techniques to dissect the functions of two proximal E-box sites at −165 and +44 nt in regulating the hTERT promoter in the native genomic contexts. Our data showed that mutations of these sites abolished promoter binding by c-Myc/Max, USF1 and USF2, decreased hTERT promoter activity, and prevented its activation by overexpressed c-Myc. Upon inhibition of histone deacetylases, mutant and wildtype promoters were induced to the same level, indicating that the E-boxes functioned to de-repress the hTERT promoter and allowed its transcription in a repressive chromatin environment. Unexpectedly, knockdown of endogenous c-Myc/Max proteins activated hTERT promoter. This activation did not require the proximal E-boxes but was accompanied by increased promoter accessibility, as indicated by augmented active histone marks and binding of multiple TFs at the promoter. Our studies demonstrated that c-Myc/Max functioned in maintaining chromatin-dependent repression of the hTERT gene in addition to activating its promoter. |
| publisher |
Oxford University Press |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176324/ |
| _version_ |
1613137725477617664 |