Histone acetyltransferase and genetic integrity of the male gamete

雄性和雌性配子是新个体的基础，它们完整的基因组确保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。这一过程的单倍体阶段称为“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。我们已经清楚地表明，在小鼠和人类的瞬时DNA链断裂出现在整个人口的精子细胞前体（精子细胞），是一致的染色质重塑的主要步骤。任何瞬时链断裂的发生都代表着对DNA完整性的潜在威胁，而染色质重塑这一重要步骤的致突变潜力迄今为止一直被忽视。这一过程中的扰动可能导致遗传改变，对胚胎的生育能力或遗传疾病产生巨大影响。在精子发生过程中，通常包装DNA的组蛋白在生化修饰（乙酰化）后被撤回。乙酰化是为了创造一个短暂的DNA敏感性状态，允许链断裂。我们发现了一种能够乙酰化组蛋白的新型酶，它可能在DNA链断裂的形成中发挥作用。这种酶，称为溶血磷脂酸酰基转移酶α（LPAAT α），通常参与脂质代谢，但现在令人惊讶地发现在精子细胞的细胞核中。该项目旨在研究LPAAT alpha和其他酰基转移酶在控制组蛋白乙酰化和DNA断裂形成中的新核作用，首次将脂质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 During spermiogenesis, the histones, which normally package DNA, are withdrawn following a biochemical modification (acetylation).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.