组蛋白置换对重编程细胞染色质结构的调控作用

Cell reprogramming greatly changes the structure of chromatin, which consists of DNA and histones. There are multiple histone variants, which replace canonical histones during reprogramming in human cells. This histone replacement has been considered to be critical in regulating the dynamic changes in chromatin structure, but its underlying mechanisms remain unclear. Spermatogenesis also involves epigenetic reprogramming. After meiosis of male germ cells, the majority of histones are replaced by protamines. The applicant’s recent results demonstrate that the histone replacement in spermatids is caused by the acetylation-mediated proteasomal degradation of the core histones (Qian et al., Cell, 2013). This project will focus on the mechanisms by which histone degradation or replacement regulates the dynamic changes in chromatin structure during cell reprogramming. The results from this project will improve our understanding of epigenetic regulation during cell reprogramming, and provide a basis for illustrating the molecular mechanism for cell growth, the directed differentiation, and the induction of pluripotent stem cells, for exploring the mechanisms underlying the formation and development of certain diseases, such as cancer, and for discovering the related therapeutic drugs.

细胞重编程使由DNA和组蛋白共同组成的染色质的结构发生了巨大改变。组蛋白在人类细胞中具有多种变体，在重编程过程中可取代常规的组蛋白。这种组蛋白置换已被认为是调控染色质结构动态变化的关键机制之一，而其机理仍有待于进一步研究。精子发生其实也是一种表观遗传信息的重编程过程。男性生殖细胞在减数分裂后，绝大多数组蛋白会被精蛋白取而代之。申请者最新研究结果表明，精细胞中组蛋白置换是由依赖于乙酰化的核心组蛋白通过蛋白酶体降解引起的（Qian et al., Cell, 2013）。本项目将重点研究通过组蛋白置换（或降解）调控细胞重编程过程中染色质高级结构的动态变化机制。其结果将加深对细胞重编程过程表观遗传调控机制的认识，为阐明细胞生长、定向分化和诱导性多能干细胞形成的分子机制、解析相关疾病（如癌症）发生发展的机理及药物研发提供理论基础。

项目负责人前期研究发现多数哺乳动物睾丸中的蛋白酶体包含激活因子PA200、睾丸特异的α亚基α4s及免疫蛋白酶体的β催化亚基，组成特异的“生精蛋白酶体” （Qian et al., Cell, 2013）。本项目原计划研究内容主要为探索生精蛋白酶体亚基α4s在精子发生过程中组蛋白降解中的作用，阐明全能干细胞中组蛋白是否降解，并揭示重编程细胞中组蛋白置换的机制。项目执行三年来，基本完成了原计划研究内容，具体结果包括：1）揭示了睾丸特异蛋白酶体亚基α4s为精子发生和该过程中组蛋白降解所必需，2）发现了PA200促进体细胞DNA损伤修复和精子发生过程中核心组蛋白降解时的共同激活因子，3）证明PA200及其共同激活因子在细胞重编程过程中组蛋白的降解中起着关键作用。本项目的大部分结果仍在整理中，近期会投稿。在项目执行期间已发表的Nature Immunology (2015)等4篇论文已标注该项目，另一篇标注该项目的研究论文已投稿（审稿中）。这些结果将加深对细胞重编程过程表观遗传调控机制的认识，为阐明细胞生长、定向分化和诱导性多能干细胞形成的分子机制、解析相关疾病（如癌症和男性不育症）发生发展的机理及药物研发提供理论基础。