Broad Institute of MIT and Harvard, Cambridge, United States.
Division of Hematology/Oncology, Department of Medicine; Bakar Computational Health Sciences Institute; Institute for Human Genetics; University of California, San Francisco, San Francisco, United States.
Elife. 2021 Sep 6;10:e66198. doi: 10.7554/eLife.66198.
In cancer, telomere maintenance is critical for the development of replicative immortality. Using genome sequences from the Cancer Cell Line Encyclopedia and Genomics of Drug Sensitivity in Cancer Project, we calculated telomere content across 1299 cancer cell lines. We find that telomerase reverse transcriptase () expression correlates with telomere content in lung, central nervous system, and leukemia cell lines. Using CRISPR/Cas9 screening data, we show that lower telomeric content is associated with dependency of CST telomere maintenance genes. Increased dependencies of shelterin members are associated with wild-type status. Investigating the epigenetic regulation of , we find widespread allele-specific expression in promoter-wildtype contexts. promoter-mutant cell lines exhibit hypomethylation at PRC2-repressed regions, suggesting a cooperative global epigenetic state in the reactivation of telomerase. By incorporating telomere content with genomic features across comprehensively characterized cell lines, we provide further insights into the role of telomere regulation in cancer immortality.
在癌症中，端粒维持对于复制性永生的发展至关重要。我们利用来自癌症细胞系百科全书和癌症药物敏感性基因组学项目的基因组序列，计算了 1299 种癌细胞系中的端粒含量。我们发现端粒酶逆转录酶（）的表达与肺癌、中枢神经系统和白血病细胞系中的端粒含量相关。通过使用 CRISPR/Cas9 筛选数据，我们表明较低的端粒含量与 CST 端粒维持基因的依赖性相关。庇护素成员的依赖性增加与野生型状态相关。研究端粒酶的表观遗传调控，我们发现启动子野生型情况下存在广泛的等位基因特异性表达。端粒酶突变的细胞系在 PRC2 抑制区域表现出低甲基化，这表明在端粒酶的重新激活中存在协同的全局表观遗传状态。通过将端粒含量与经过全面表征的细胞系中的基因组特征相结合，我们进一步深入了解了端粒调控在癌症永生中的作用。
