Abstract
A novel antisense transcript was identified in the human telomerase reverse transcriptase (hTERT) promoter region, suggesting that the hTERT promoter is bidirectional. This transcript, named hTERT antisense promoter-associated (hTAPAS) RNA, is a 1.6 kb long non-coding RNA. hTAPAS transcription is initiated 167 nucleotides upstream of the hTERT transcription start site and is present in both the nucleus and the cytoplasm. Surprisingly, we observed that a large fraction of the hTERT polyadenylated RNA is localized in the nucleus, suggesting this might be an additional means of regulating the cellular abundance of hTERT protein. Both hTAPAS and hTERT are expressed in immortalized B-cells and human embryonic stem cells but are not detected in normal somatic cells. hTAPAS expression inversely correlates with hTERT expression in different types of cancer samples. Moreover, hTAPAS expression is not promoted by an hTERT promoter mutation (-124 C>T). Antisense-oligonucleotide mediated knockdown of hTAPAS results in an increase in hTERT expression. Conversely, ectopic overexpression of hTAPAS down regulates hTERT expression, suggesting a negative role in hTERT gene regulation. These observations provide insights into hTAPAS as a novel player that negatively regulates hTERT expression and may be involved in telomere length homeostasis.
Highlights
Telomerase activity and telomere length have important implications in human disease and aging [1]; elevated telomerase activity has been detected in most human cancers [2,3,4]
Deep sequencing of transcriptomes from chickens revealed an antisense transcript upstream of TERT, which is an alternatively spliced, polyadenylated, lncRNA named TERT antisense promoter-associated (TAPAS) [16]; this suggests that the TERT promoter is bidirectional
An antisense RNA in the human telomerase reverse transcriptase (hTERT) promoter region was readily observed in two different human B-cell tumor lines (GM12878 and OCI-LY7) (Figure 1 and Figure S1)
Summary
Telomerase activity and telomere length have important implications in human disease and aging [1]; elevated telomerase activity has been detected in most human cancers [2,3,4]. Expression of human telomerase reverse transcriptase (hTERT), the enzymatic component of telomerase, is tightly regulated at the transcriptional level through epigenetic modifications in the promoter region [5], as well through alternative splicing [6,7,8]. The hTERT promoter has many features characteristic of bidirectional promoters, such as the absence of a TATA box and high GC content [12], as well as binding sites for the ETS transcription factor GA binding protein (GABP) [13,14]. Recent data demonstrate that the mutant hTERT promoter can be bound and activated by GABP [15], suggesting it may induce bidirectional transcription of an antisense transcript
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