Multiple independent sequence variants of the hTERT locus have been associated with telomere length and cancer risks in genome-wide association studies. Here, we identified an intronic variable number tandem repeat, VNTR2-1, as an enhancer-like element, which activated hTERT transcription in a cell in a chromatin-dependent manner. VNTR2-1, consisting of 42-bp repeats with an array of enhancer boxes, cooperated with the proximal promoter in the regulation of hTERT transcription by basic helix–loop–helix transcription factors and maintained hTERT expression during embryonic stem-cell differentiation. Genomic deletion of VNTR2-1 in MelJuSo melanoma cells markedly reduced hTERT transcription, leading to telomere shortening, cellular senescence, and impairment of xenograft tumor growth. Interestingly, VNTR2-1 lengths varied widely in human populations; hTERT alleles with shorter VNTR2-1 were underrepresented in African American centenarians, indicating its role in human aging. Therefore, this polymorphic element is likely a missing link in the telomerase regulatory network and a molecular basis for genetic diversities of telomere homeostasis and age-related disease susceptibilities.

在全基因组关联研究中， hTERT位点的多个独立序列变异与端粒长度和癌症风险相关。在这里，我们鉴定了一个内含子可变数量串联重复序列 VNTR2-1，作为增强子样元件，它以染色质依赖性方式激活细胞中的 hTERT 转录。 VNTR2-1由42 bp重复序列和一系列增强子盒组成，通过基本螺旋-环-螺旋转录因子与近端启动子配合调节hTERT转录，并在胚胎干细胞分化过程中维持hTERT表达。 MelJuSo 黑色素瘤细胞中 VNTR2-1 的基因组缺失显着降低了 hTERT 转录，导致端粒缩短、细胞衰老和异种移植肿瘤生长受损。有趣的是，VNTR2-1 的长度在人群中差异很大。具有较短 VNTR2-1 的hTERT等位基因在非裔美国百岁老人中所占比例不足，表明其在人类衰老中的作用。因此，这种多态性元件可能是端粒酶调节网络中缺失的一环，也是端粒稳态遗传多样性和年龄相关疾病易感性的分子基础。