The Guy Hilton Research Laboratories, School of Pharmacy and Bioengineering, Faculty of Medicine and Health Sciences, Keele University, Stoke on Trent ST4 7QB, U.K.
Emerg Top Life Sci. 2021 Oct 29;5(4):497-505. doi: 10.1042/ETLS20200344.
The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.
端粒的表观遗传性质仍存在争议，不同的人类细胞系在端粒上可能表现出不同的组蛋白标记。表观遗传修饰调节端粒长度和端粒酶活性，影响端粒结构和维持。端粒酶负责端粒的伸长和维持，其最小组成部分是催化蛋白成分端粒酶逆转录酶（TERT）和模板形成 RNA 成分端粒酶 RNA（TERC）。TERT 启动子突变可能是端粒酶激活的基础，但由于表观遗传、转录和转录后修饰的复杂相互作用，该基因的调控仍不完全清楚。多能干细胞（PSCs）可以通过其内源端粒酶活性、端粒长度的维持和体外复制性衰老的旁路来维持无限的、不朽的增殖潜力。PSCs 的分化导致 TERT 基因沉默，并整体恢复为有丝分裂细胞表型。这种受控转录沉默的精确机制很复杂。启动子甲基化与端粒酶调控的表观遗传控制有关，这为理解癌症和干细胞生物学提供了一个重要的前景。在 PSCs 的分化过程中端粒酶的下调受到控制，为研究其内源调控提供了一个方便的模型。端粒酶的重新激活有可能逆转组织退化，促进修复，并成为未来组织工程策略的一个组成部分。综上所述，PSCs 为全面了解端粒酶调控提供了一个独特的系统，并将这一知识推进到衰老和治疗应用中。
