Histone acetyltransferase and genetic integrity of the male gamete

雄配子和雌配子是新个体的基础，它们完整的基因组确保将遗传信息忠实地传递给下一代。精子发生过程中雄配子的产生是一个复杂的分化过程。这个过程的单倍体阶段被称为“精子发生”，其特征是染色质的重要重组涉及DNA包装的重大变化。我们已经清楚地证明，在小鼠和人类中，一过性DNA链断裂出现在整个精子细胞前体(精子细胞)群体中，并且与染色质重塑的主要步骤一致。任何一过性链断裂的发生都是对DNA完整性的潜在威胁，而染色质重塑这一重要步骤的突变潜力迄今仍被忽视。这一过程中的干扰可能会导致基因改变，对生育能力或胚胎的遗传障碍产生戏剧性后果。在精子发生过程中，通常包裹DNA的组蛋白在生化修饰(乙酰化)后被提取。然而，乙酰化产生了一种瞬间的DNA敏感性，允许链断裂。我们发现了一种新的能够乙酰化组蛋白的酶，它可能在DNA链断裂的形成中发挥作用。这种酶被称为溶血磷脂酸酰基转移酶α(LPAATα)，通常与脂质代谢有关，但现在令人惊讶的是在精子细胞的细胞核中发现了这种酶。本项目旨在研究LPAATα和其他酰基转移酶在控制组蛋白乙酰化和DNA断裂形成中的新核心作用，首次将脂代谢与染色质动力学联系起来。

The male and female gametes are the basis of a new individual and their intact genomes ensure faithful transmission of genetic information to the next generation. The production of the male gamete during spermatogenesis is a complex differentiation process. The haploid phase of this process termed "spermiogenesis" is characterized by an important restructuring of the chromatin involving a major change in DNA packaging. We have clearly demonstrated that in both mouse and humans transient DNA strand breaks appear in the whole population of sperm cells precursors (spermatids) and are coincident with the major steps of chromatin remodeling. Any occurrence of transient strand breakage represents a potential threat to DNA integrity and the mutagenic potential of this important step of chromatin remodeling has been so far overlooked. Perturbations in the process can lead to genetic alterations with dramatic consequences for fertility or genetic disorders of the embryo. During spermiogenesis, the histones, which normally package DNA, are withdrawn following a biochemical modification (acetylation). Acetylation is though to create a transient state of DNA sensitivity allowing strand breakage. We identified a novel enzyme able to acetylate histone and that may play a role in the formation of DNA strand breaks. This enzyme, termed lysophosphatidic acid acyltransferase alpha (LPAATalpha), is normally involved in lipid metabolism but is now surprisingly found in the nuclei of spermatids. This project aims to study the new nuclear role of LPAATalpha and other acyltransferases in controlling histone acetylation and the formation of DNA breaks linking for the first time lipid metabolism to chromatin dynamics.