The role of macroH2A variants in cancer and senescence

项目摘要 大分子H_2A1型组蛋白变体(包括大分子H_2A1.1和大分子H_2A1.2)在 抑制肿瘤、衰老、激活和抑制转录、促进DNA修复和 抑制将分化细胞重新编程为干细胞。大分子H2 A的典型特征是 柔性接头将组蛋白H_2A样区融合到C-末端大结构域，即配体结合域 其功能是通过与一个聚腺苷二磷酸核糖家族产生的聚腺苷二磷酸核糖结合来调节的 聚合酶。MacroH2A1调节其大染色质结构域中发现的基因的表达 可以跨越数百个千碱基。MacroH2A1也在调节基因表达方面发挥关键作用 癌基因诱导衰老是一种重要的肿瘤抑制机制。有趣的是，在 衰老是一种内质网应激依赖机制，需要DNA损伤信号激酶ATM导致 大分子H_2A1基因组分布的全基因组变化，类似于癌细胞的变化。穿过 其表达的变化和/或基因组定位的改变，对宏H_2A1‘S肿瘤的干扰 抑制功能在癌症中很常见；宏H2A转录和剪接的变化 可见于多种癌症，包括肺癌、乳腺癌、结肠癌、卵巢癌、子宫内膜癌、膀胱癌、 睾丸和黑素细胞。始终如一地，原代细胞中宏H2A1的丢失足以引发 致癌基因表达谱。 本项目的总体目标是阐明大分子H_2A1在基因调控中的作用。 在正常和衰老细胞中的表达，并确定宏H_2A1的功能失调 有助于基因表达的改变，从而允许衰老旁路和肿瘤发生。各种各样的 创新的反向遗传学、药理学和全基因组方法将用于追求 这些目标。第一个目标将确定大分子H_2A1变异调控的机制。 正常细胞和衰老细胞中的转录。第二个目标将决定ATM的机制 衰老过程中内质网应激的激活和大分子H_2A1的动员。第三个目标将是 通过用RNA POL II延伸率调节宏H_2A1剪接来确定其机制。《知识》 关于宏H_2A1介导的基因表达调控、基因组定位和宏H_2A1剪接 从这项提议中获得的监管将有助于解释宏观H_2A1功能如何变得失调 在肿瘤形成过程中。

Project Summary The macroH2A1-type histone variants (which include macroH2A1.1 and macroH2A1.2) have roles in tumor suppression, senescence, activation and repression of transcription, promotion of DNA repair and suppression of the reprogramming of differentiated cells into stem cells. MacroH2As are typified by a histone H2A-like region fused by a flexible linker to a C-terminal macrodomain, a ligand-binding domains whose functions are modulated by binding to poly(ADP-ribose) produced by a family of poly(ADP-ribose) polymerases. MacroH2A1 regulates the expression of genes found within its large chromatin domains which can span hundreds of kilobases. MacroH2A1 also plays a critical role in regulating gene expression during oncogene-induced senescence, an important tumor suppressive mechanisms. Interestingly, during senescence an ER stress-dependent mechanism requiring the DNA damage signaling kinase ATM leads to genome-wide changes in macroH2A1 genomic distribution which resemble that of cancer cells. Through changes in its expression and/or alterations in its genomic localization, disruption of macroH2A1’s tumor suppressive functions is common in cancer; alterations of macroH2A transcription and splicing have been observed in a variety of cancers including those of lung, breast, colon, ovaries, endometrium, bladder, testicles, and melanocytes. Consistently, macroH2A1 loss in primary cells is sufficient to trigger an oncogenic gene expression profile. The overall goals of this project are to elucidate the function of macroH2A1in the regulation of gene expression in normal and senescent cells and to determine how dysregulation of macroH2A1 function contributes to alterations in gene expression that allow senescence-bypass and oncogenesis. A variety of innovative reverse genetics, pharmacological and genome-wide approaches will be used in the pursuit of these goals. The first aim will determine the mechanisms by which macroH2A1 variants regulate transcription in normal and senescent cells. The second aim will determine the mechanism of ATM activation and macroH2A1 mobilization in response to ER stress during senescence. The third aim will determine the mechanism by with RNA Pol II elongation rate regulates macroH2A1 splicing. The knowledge about macroH2A1-mediated regulation of gene expression, genomic localization and macroH2A1 splicing regulation gained from this proposal will help to explain how macroH2A1 function becomes dysregulated during oncogenesis.