Our long-term goal is to understand the critical steps of hTERT gene regulation during development. The hTERT gene, which encodes the rate-limiting subunit of human telomerase, is expressed at a high level in embryonic tissues and stem cells, but is repressed upon differentiation in the majority of adult somatic cells. Although the hTERT promoter has been studied extensively, the contribution of chromatin environment and the requirement of cis-elements have not been determined for the repression of the endogenous hTERT transcription. Previous results, including our own, have indicated that native chromatin plays a critical role in the regulation of hTERT transcription. hTERT transcription can be reversibly induced by inhibition of histone deacetylases and this induction is accompanied by chromatin remodeling at the hTERT promoter. Furthermore, we and others have shown that transiently transfected plasmid reporters are not ideal models for the repression of endogenous hTERT gene in somatic cells. Based on these findings, we hypothesize that chromatin environment is a critical component of the regulatory mechanisms for the repression of the native hTERT promoter. Here, we plan to study the molecular details of hTERT repression in a chromatin context using TPA-induced U937 cell differentiation as a model. We propose to pursue three interconnected aims: (1) To determine the role of global chromatin environment in hTERT repression during differentiation; (2) To determine sequential events of nuclear factor recruitment and histone modifications that occur at the hTERT core promoter region during differentiation. (3) To create a novel chromosome-based reporter system and dissect the roles of cis-regulatory elements in hTERT repression.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071725-02
Application #
6916309
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Carter, Anthony D
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$259,507
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Cheng, De; Wang, Shuwen; Jia, Wenwen et al. (2017) Regulation of human and mouse telomerase genes by genomic contexts and transcription factors during embryonic stem cell differentiation. Sci Rep 7:16444
Cheng, De; Zhao, Yuanjun; Wang, Shuwen et al. (2017) Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes. FASEB J 31:1165-1178
Zhang, Fan; Cheng, De; Wang, Shuwen et al. (2016) Human Specific Regulation of the Telomerase Reverse Transcriptase Gene. Genes (Basel) 7:
Cheng, De; Zhao, Yuanjun; Wang, Shuwen et al. (2015) Human Telomerase Reverse Transcriptase (hTERT) Transcription Requires Sp1/Sp3 Binding to the Promoter and a Permissive Chromatin Environment. J Biol Chem 290:30193-203
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Yaswen, Paul; MacKenzie, Karen L; Keith, W Nicol et al. (2015) Therapeutic targeting of replicative immortality. Semin Cancer Biol 35 Suppl:S104-S128
Ma, Yanchun; Hao, Sijie; Wang, Shuwen et al. (2015) A Combinatory Strategy for Detection of Live CTCs Using Microfiltration and a New Telomerase-Selective Adenovirus. Mol Cancer Ther 14:835-43
Zhao, Yuanjun; Cheng, De; Wang, Shuwen et al. (2014) Dual roles of c-Myc in the regulation of hTERT gene. Nucleic Acids Res 42:10385-98
Zhao, Yuanjun; Wang, Shuwen; Zhu, Jiyue (2011) A multi-step strategy for BAC recombineering of large DNA fragments. Int J Biochem Mol Biol 2:199-206
Jia, Wenwen; Wang, Shuwen; Horner, James W et al. (2011) A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis. FASEB J 25:979-89

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