Regulation of the Human Telomerase Gene TERT by Telomere Position Effect—Over Long Distances (TPE-OLD): Implications for Aging and Cancer

Telomerase is expressed in early human development and then becomes silenced in most normal tissues. Because ~90% of primary human tumors express telomerase and generally maintain very short telomeres, telomerase is carefully regulated, particularly in large, long-lived mammals. In the current report, we provide substantial evidence for a new regulatory control mechanism of the rate limiting catalytic protein component of telomerase (hTERT) that is determined by the length of telomeres. We document that normal, young human cells with long telomeres have a repressed hTERT epigenetic status (chromatin and DNA methylation), but the epigenetic status is altered when telomeres become short. The change in epigenetic status correlates with altered expression of TERT and genes near to TERT, indicating a change in chromatin. Furthermore, we identified a chromosome 5p telomere loop to a region near TERT in human cells with long telomeres that is disengaged with increased cell divisions as telomeres progressively shorten. Finally, we provide support for a role of the TRF2 protein, and possibly TERRA, in the telomere looping maintenance mechanism through interactions with interstitial TTAGGG repeats. This provides new insights into how the changes in genome structure during replicative aging result in an increased susceptibility to age-related diseases and cancer prior to the initiation of a DNA damage signal.端粒酶（telomerase）在人类早期发育阶段表达，随后在绝大多数正常组织中被沉默。由于约90%的原发性人类肿瘤均表达端粒酶且通常维持极短的端粒，端粒酶的调控过程受到严格管控，这一点在大型长寿命哺乳动物中尤为显著。在本研究中，我们为端粒酶的限速催化蛋白组分——人类端粒酶逆转录酶（hTERT）的全新调控机制提供了充分实验证据，该调控机制由端粒长度决定。本研究证实，端粒较长的正常年轻人类细胞呈现hTERT的表观遗传抑制状态（涵盖染色质修饰与DNA甲基化调控），但当端粒逐渐缩短时，该表观遗传状态会发生改变。该表观遗传状态的改变与TERT基因及其邻近基因的表达变化相关，提示染色质状态发生了重塑。此外，我们在端粒较长的人类细胞中，发现了一条指向TERT基因邻近区域的5号染色体短臂（chromosome 5p）端粒环；随着细胞分裂次数增加、端粒逐步缩短，该端粒环会发生解离。最后，本研究为TRF2蛋白（TRF2 protein）以及可能存在的TERRA（TERRA）通过与间隙TTAGGG重复序列相互作用，维持端粒环结构稳定的功能提供了实验支持。该研究为解析复制性衰老过程中基因组结构改变如何在DNA损伤信号启动前，提升机体对年龄相关性疾病与癌症的易感性，提供了全新的认知视角。