Division of Hematology/Oncology, Children's Hospital Boston, Massachusetts 02115, USA.
Nature. 2010 Mar 11;464(7286):292-6. doi: 10.1038/nature08792. Epub 2010 Feb 17.
Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues. Patient-specific induced pluripotent stem (iPS) cells represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT). We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3' deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.
先天性角化不良症（DC）患者存在端粒维持障碍，会导致多种组织退化。患者特异性诱导多能干细胞（iPS）是研究人类退行性疾病（如 DC）的宝贵体外模型。iPS 细胞的一个主要特征是获得无限的自我更新能力，同时伴随着端粒酶逆转录酶基因（TERT）的诱导。我们研究了端粒酶功能缺陷是否会限制 DC 患者 iPS 细胞的诱导和维持。本研究表明，重编程后的 DC 细胞克服了端粒酶 RNA 成分（TERC）水平的关键限制，从而恢复端粒维持和自我更新。我们发现，TERC 上调是多能性的一个特征，几个端粒酶成分是多能性相关转录因子的靶点，并且在常染色体显性 DC 中，转录沉默伴随着 TERC 基因座 3'端缺失。我们的结果表明，尽管端粒酶的遗传缺陷会影响端粒延长，但重编程仍能恢复 DC 细胞的端粒伸长，并表明增加 TERC 表达的策略可能对 DC 患者具有治疗益处。
