García-Cao Marta, O'Sullivan Roderick, Peters Antoine H F M, Jenuwein Thomas, Blasco María A
Molecular Oncology Program, Spanish National Cancer Centre (CNIO), E-28029 Madrid, Spain.
Nat Genet. 2004 Jan;36(1):94-9. doi: 10.1038/ng1278. Epub 2003 Dec 14.
Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins. Telomeres are heterochromatic regions. Yeast and flies with defects in activities that modify the state of chromatin also have abnormal telomere function, but the putative role of chromatin-modifying activities in regulating telomeres in mammals is unknown. Here we report on telomere length and function in mice null with respect to both the histone methyltransferases (HMTases) Suv39h1 and Suv39h2 (called SUV39DN mice). Suv39h1 and Suv39h2 govern methylation of histone H3 Lys9 (H3-Lys9) in heterochromatic regions. We show that primary cells derived from SUV39DN mice have abnormally long telomeres relative to wild-type controls. Using chromatin immunoprecipitation (ChIP) analysis, we found that telomeres were enriched in di- and trimethylated H3-Lys9 but that telomeres of SUV39DN cells had less dimethylated and trimethylated H3-Lys9 but more monomethylated H3-Lys9. Concomitant with the decrease in H3-Lys9 methylation, telomeres in SUV39DN cells had reduced binding of the chromobox proteins Cbx1, Cbx3 and Cbx5, homologs of Drosophila melanogaster heterochromatin protein 1 (HP1). These findings indicate substantial changes in the state of telomeric heterochromatin in SUV39DN cells, which are associated with abnormal telomere elongation. Taken together, the results indicate epigenetic regulation of telomere length in mammals by Suv39h1 and Suv39h2.
端粒是真核染色体末端的帽状结构，由与一系列特殊蛋白质结合的TTAGGG重复序列组成。端粒是异染色质区域。酵母和果蝇中影响染色质状态的活性存在缺陷时，端粒功能也会异常，但染色质修饰活性在调节哺乳动物端粒中的假定作用尚不清楚。在此，我们报告了组蛋白甲基转移酶（HMTases）Suv39h1和Suv39h2均缺失的小鼠（称为SUV39DN小鼠）的端粒长度和功能。Suv39h1和Suv39h2控制异染色质区域组蛋白H3赖氨酸9（H3-Lys9）的甲基化。我们发现，相对于野生型对照，源自SUV39DN小鼠的原代细胞具有异常长的端粒。通过染色质免疫沉淀（ChIP）分析，我们发现端粒富含二甲基化和三甲基化的H3-Lys9，但SUV39DN细胞的端粒中二甲基化和三甲基化的H3-Lys9较少，而一甲基化的H3-Lys9较多。伴随着H3-Lys9甲基化的减少，SUV39DN细胞中的端粒与染色体盒蛋白Cbx1、Cbx3和Cbx5（果蝇黑腹异染色质蛋白1（HP1）的同源物）的结合减少。这些发现表明SUV39DN细胞中端粒异染色质状态发生了实质性变化，这与端粒异常延长有关。综上所述，结果表明Suv39h1和Suv39h2对哺乳动物端粒长度进行表观遗传调控。
