title: Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes.
abstract: The human telomerase reverse transcriptase (hTERT) gene is repressed in most somatic cells, whereas the expression of the mousemTertgene is widely detected. To understand the mechanisms of this human-specific repression, we constructed bacterial artificial chromosome (BAC) reporters using human and mouse genomic DNAs encompassing theTERTgenes and neighboring loci. Upon chromosomal integration, the hTERT, but not the mTert, reporter was stringently repressed in telomerase-negative human cells in a histone deacetylase (HDAC)-dependent manner, replicating the expression of their respective endogenous genes. In chimeric BACs, the mTert promoter became strongly repressed in the human genomic context, but the hTERT promoter was highly active in the mouse genomic context. Furthermore, an unrelated herpes simplex virus-thymidine kinase (HSV-TK) promoter was strongly repressed in the human, but not in the mouse, genomic context. These results demonstrated that the repression ofhTERTgene was dictated by distal elements and its chromatin environment. This repression depended on class I HDACs and involved multiple corepressor complexes, including HDAC1/2-containing Sin3B, nucleosome remodeling and histone deacetylase (NuRD), and corepressor of RE1 silencing transcription factor (CoREST) complexes. Together, our data indicate that the lack of telomerase expression in most human somatic cells results from its repressive genomic environment, providing new insight into the mechanism of long-recognized differential telomerase regulation in mammalian species.-Cheng, D., Zhao, Y., Wang, S., Zhang, F., Russo, M., McMahon, S. B., Zhu, J. Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes.
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA.
authors.forename: De
authors.lastname: Cheng
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; and.
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; and.
authors.forename: Mariano
authors.initials: M
authors.lastname: Russo
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington, USA; jiyue.zhu@wsu.edu.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D015894:Genome, Human; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D011401:Promoter Regions, Genetic; D013045:Species Specificity; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
chemical_list: C509186:TERT protein, human; D019098:Telomerase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1