TY - JOUR
T1 - Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene
AU - Xu, Tao
AU - Cheng, De
AU - Zhao, Yuanjun
AU - Zhang, Jinglong
AU - Zhu, Xiaolu
AU - Zhang, Fan
AU - Chen, Gang
AU - Wang, Yang
AU - Yan, Xiufeng
AU - Robertson, Gavin P.
AU - Gaddameedhi, Shobhan
AU - Lazarus, Philip
AU - Wang, Shuwen
AU - Zhu, Jiyue
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported in part by NIH Grant R01GM071725 to J. Zhu, Team Science Award Grant 579152 from the Melanoma Research Alliance to J. Zhu, G.P.R., and S.G., and the Health Sciences and Services Authority of Spokane County. We thank Chloe A. Dugger for technical assistance and Drs. Tianjie Pu and Boyang Wu for assistance with tumor histological analysis. We also thank the Program of Laboratory Animal Resources and the Histology Core of Washington State University (WSU) Spokane and the Genomics Core at WSU Pullman.
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/6/29
Y1 - 2021/6/29
N2 - Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genomewide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element,which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of enhancer boxes, cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix-loop-helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations; hTERT alleles with shorter VNTR2-1 were underrepresented in African American centenarians, indicating its role in human aging. Therefore, this polymorphic element is likely a missing link in the telomerase regulatory network and a molecular basis for genetic diversities of telomere homeostasis and age-related disease susceptibilities.
AB - Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genomewide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element,which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of enhancer boxes, cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix-loop-helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations; hTERT alleles with shorter VNTR2-1 were underrepresented in African American centenarians, indicating its role in human aging. Therefore, this polymorphic element is likely a missing link in the telomerase regulatory network and a molecular basis for genetic diversities of telomere homeostasis and age-related disease susceptibilities.
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U2 - 10.1073/pnas.2019043118
DO - 10.1073/pnas.2019043118
M3 - Article
C2 - 34155099
AN - SCOPUS:85108311918
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 26
M1 - e2019043118
ER -
