Grupo de Telomerasa, Cáncer y Envejecimiento, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.
Instituto Murciano de Investigación Biosanitaria-Arrixaca, 30120 Murcia, Spain.
Proc Natl Acad Sci U S A. 2021 Aug 10;118(32). doi: 10.1073/pnas.2015528118.
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Here, we report that zebrafish telomerase RNA () binds to specific DNA sequences of master myeloid genes and controls their expression by recruiting RNA Polymerase II (Pol II). Zebrafish harboring the CR4-CR5 domain mutation found in DC patients hardly interacted with Pol II and failed to regulate myeloid gene expression in vivo and to increase their transcription rates in vitro. Similarly, regulated myeloid gene expression and Pol II promoter occupancy in human myeloid progenitor cells. Strikingly, induced pluripotent stem cells derived from DC patients with a mutation in the CR4-CR5 domain showed impaired myelopoiesis, while those with mutated telomerase catalytic subunit differentiated normally. Our findings show that acts as a transcription factor, revealing a target for therapeutic intervention in DC patients.
先天性角化不良症（DC）是一种罕见的遗传性骨髓衰竭和癌症易感性综合征，由端粒酶或端粒蛋白的突变引起。在这里，我们报告说，斑马鱼端粒酶 RNA () 与主髓样基因的特定 DNA 序列结合，并通过招募 RNA 聚合酶 II (Pol II) 来控制其表达。携带在 DC 患者中发现的 CR4-CR5 结构域突变的斑马鱼几乎不与 Pol II 相互作用，无法在体内调节髓样基因表达，也无法在体外提高其转录速率。同样， 调节人类髓样祖细胞中的髓样基因表达和 Pol II 启动子占据。引人注目的是，源自 CR4-CR5 结构域中存在 突变的 DC 患者的诱导多能干细胞表现出受损的髓样生成，而那些具有突变的端粒酶催化亚基的细胞则正常分化。我们的研究结果表明， 作为一种转录因子发挥作用，为 DC 患者的治疗干预提供了一个靶点。
