Telomerase is a
ribonucleoprotein enzyme that synthesizes telomere end sequence. The expression of hTERT gene, encoding the catalytic subunit of human
telomerase, is restricted to highly proliferative tissues and is undetectable in most somatic cells. Abnormal activation of hTERT gene is found in 90% of human
tumors. Previously, we identified tandem repeat of 42-bp/unit, VNTR2-1, in intron 2 of the hTERT gene, as a novel regulatory
element important for hTERT transcription in
cancer cells. In the current study, we found that multiple 42-bp repeats of VNTR2-1 activated
luciferase gene in reporter plasmids. Mutation of the predicted cis-regulatory elements within the 42-bp repeats, including a E-box motif, resulted in a partial or complete loss of its enhancer activity. Moreover, MYC family
proteins, c-MYC, MAX, and MNT, regulated hTERT gene transcription through both VNTR2-1 and E-boxes at the proximal hTERT promoter.
Chromatin segmentation analysis of published ChIP-sequencing data from K562 cells indicated that VNTR2-1 was a bivalent enhancer. In
telomerase-expressing human
melanoma cell line MelJuSo, deletion of VNTR2-1 caused the hTERT promoter
chromatin status to change from an active state to a repressed state, accompanied by increases of H3K27me3 and H3K9me3 marks. Therefore, we provided additional evidence for VNTR2-1 as a functional regulatory
element that regulated hTERT expression by MYC family
transcription factors. These results have improved our knowledge on the functions of repetitive genomic DNAs and the regulatory mechanisms of human
telomerase gene.