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A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis
Abstract
Telomerase is tightly regulated in humans relative to mice, owing to the differential regulation of TERT genes. To explore hTERT regulation in vivo,we engineered mice with a 160‐kb transgenic bacterial artificial chromosome (BAC) spanning the hTERT locus with a ReniUa luciferase ( Rluc ) cassette downstream of its promoter. Analysis of multiple founder lines revealed that the Rluc expression profile from the transgenic hTERT reporter locus reproduced that of the native hTERT gene in all tissues and organs examined, demonstrating that genetic sequence determined the species‐specific developmental regulation of the hTERT gene and that mouse epigenetic and transcription machineries faithfully regulated hTERT transcription. Thus, these mice allowed detailed analyses of developmental hTERT regulation. Both the transgenic hTERT reporter and the endogenous mTERT locus were expressed in early embryonic stages, and their mRNA levels progressively decreased throughout embryonic and postnatal development. Whereas hTERT transcription was much lower than mTERT expression in most organs, it increased significantly during postnatal development of thymus, testis, and ovary. In testis, the Rluc mRNA was enriched in elongating spermatids of seminiferous tubules. Inaddition, the transcription of transgenic hTERT reporter, but surprisingly not the endogenous mTERT gene, was activated during Wnt1‐induced mammary tumorigenesis, allowing the monitoring of tumor development via noninvasive bioluminescent imaging. Collectively, our results demonstrate that the hTERT transgenic reporter system recapitulates the developmental regulation of the hTERT gene in a chromosomal position‐independent manner and serves as a legitimate model to explore telomerase regulation in the development of normal and neoplastic tissues in vivo.— Jia, W., Wang, S., Horner, J. W., Wang, N., Wang, H., Gunther, E. J., DePinho, R. A., Zhu, J. A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis. FASEB J. 25, 979–989 (2011). www.fasebj.org
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The human hTERT reporter transgene in the screening cells mirrors and recapitulates key transcriptional and functional aspects of TERT gene expression regulation in normal mouse somatic tissues.
“this human hTERT reporter transgene is capable of mirroring and recapitulating the key transcriptional and functional aspects of the regulation of TERT gene expression in normal mouse somatic tissues, thus providing a useful tool for preclinical drug screening.20”
From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [20]
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TERT activation targets DNA methylation and multiple aging hallmarks
Shim, H. S., Iaconelli, J., Shang, X., Li, J., Lan, Z. D., Jiang, S., Nutsch, K., Beyer, B. A., Lairson, L. L., Boutin, A. T., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.048 · Cited by 104
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Metadata
- Authors
- Jia, W., Wang, S., Horner, J. W., Wang, N., Wang, H., Gunther, E. J., DePinho, R. A., & Zhu, J.
- Affiliations
- Shaanxi Center for Stem Cell Engineering and Technology College of Veterinary Medicine Northwest Agriculture and Forestry (A&F) University Shaanxi China
- Department of Cellular and Molecular Physiology Hershey Pennsylvania USA
- Department of Medical Oncology Hershey Pennsylvania USA
- Jake Gittlen Cancer Research Foundation Pennsylvania State University College of Medicine Hershey Pennsylvania USA
- Belfer Institute for Applied Cancer Science Dana‐Farber Cancer Institute Harvard Medical School Boston Massachusetts USA
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2010-12-06
- Volume
- 25
- Issue
- 3
- Pages
- 979-989
- ISSN
- 0892-6638
- 1530-6860
- Cited by
- 23
- References
- 6
- Language
- en
- Funders
- National Institutes of Health (R21CA106470, R01GM071725, 2009CB941002)
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