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 themouse mTert gene is widely detected. To understand the mechanisms of this human-specific repression, weconstructedbacterial artificial chromosome(BAC)reportersusinghumanandmousegenomicDNAsencompassingthe TERT genes and neighboring loci. Upon chromosomal integration, the hTERT, but not themTert, 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 unrelatedherpes simplex virus-thymidine kinase (HSV-TK)promoterwas strongly repressed in thehuman,butnot inthe mouse,genomiccontext.These resultsdemonstratedthat therepressionofhTERTgenewasdictatedbydistalelementsand 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 fromits repressive genomic environment, providing new insight into themechanism of long-recognized differential telomerase regulation in mammalian species.