Role of the histone chaperone Nap1l1 in chromatin reorganisation during reprogramming and differentiation

早期哺乳动物发育的特征是由组蛋白及其变体的组装/拆卸介导的深刻的全局染色质变化。染色质结构的变化影响几个细胞过程，如DNA复制，转录或修复。组蛋白分子伴侣在其整个生命周期中护送组蛋白或组蛋白变体，并且参与染色质组装/拆卸，而且还参与组蛋白的核输入、储存或降解。组蛋白伴侣核小体组装蛋白1样1（Nap 1 l1）属于组蛋白伴侣Nap 1家族，其在整个真核生物中高度保守。Nap 1家族成员被描述为介导H2 A/H2 B及其变体（例如H2A.X、H2A.Z、TH 2B）的染色质组装和分解。虽然有一些关于Nap 1 l1同源物在酵母，植物和苍蝇的研究，Nap 1 l1在哺乳动物发育中的作用仍然是难以捉摸的。在这个项目中，我将阐明Nap 1 l1在小鼠发育的不同阶段中组蛋白及其变体的动态分布中的作用：1）在植入前胚胎的发育过程中，2）在原始生殖细胞的表观遗传重编程过程中，3）在多能干细胞中，4）在雄性生殖细胞的分化中。因此，我们将使用Nap 1 l1条件性基因敲除小鼠模型，在小鼠发育的特定阶段耗尽Nap 1 l1，并分析染色质组成。该项目有望揭示组蛋白伴侣Nap 1 l1的功能以及这种蛋白质如何影响发育过程中的染色质重组。更好地了解组蛋白伴侣以及它们在重编程和分化过程中如何调节染色质结构将有助于再生医学新应用的发展。

The early mammalian development is characterised by profound global chromatin changes mediated by assembly/disassembly of histones and their variants. Changes of the chromatin structure affects several cellular processes such as DNA replication, transcription or repair. Histone chaperones escort histones or histone variants throughout their life and are involved in chromatin assembly/disassembly but also in the nuclear import, storage, or degradation of histones. The histone chaperone Nucleosome assembly protein 1 like 1 (Nap1l1) belongs to the Nap1 family of histone chaperones that is highly conserved throughout eukaryotes. Nap1 family members are described to mediate chromatin assembly and disassembly of H2A/H2B and their variants (e.g. H2A.X, H2A.Z, TH2B). Although there are several studies about Nap1l1 homologs in yeast, plants and flies, the role of Nap1l1 in mammalian development has remained elusive. In this project, I will elucidate the role of Nap1l1 in the dynamic distribution of histones and their variants in different stages of mouse development: 1) during the development of the pre-implantation embryo, 2) in the process of epigenetic reprogramming in primordial germ cells, 3) in pluripotent stem cells and 4) in the differentiation of male germ cells. Therefore, we will use a Nap1l1 conditional knockout mouse model to deplete Nap1l1 in the particular stages of mouse development and analyse the chromatin composition. This project is expected to reveal critical insights into the function of the histone chaperone Nap1l1 and how this protein affects chromatin reorganisation during development. A better understanding of histone chaperones and how they regulate chromatin structure during reprogramming and differentiation will contribute to the development of new applications in regenerative medicine.