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

哺乳动物早期发育的特点是由组蛋白及其变异体的组装/分解所介导的深刻的全球染色质变化。染色质结构的改变会影响一些细胞过程，如DNA复制、转录或修复。组蛋白伴侣蛋白伴随组蛋白或组蛋白变体的一生，参与染色质的组装/分解，但也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样蛋白1(Nap111)是组蛋白伴侣蛋白NAP1家族的一员，在真核生物中高度保守。NAP1家族成员被描述为介导H_2A/H_2B及其变异体(例如H_2A.X、H_2A.Z、TH_2B)的染色质组装和拆解。虽然已经有一些关于酵母、植物和苍蝇中的Nap1l1同源物的研究，但Nap1l1在哺乳动物发育中的作用仍然不清楚。在这个项目中，我将阐明组蛋白及其变体在小鼠不同发育阶段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过程中。因此，我们将使用Nap1l1条件性基因敲除小鼠模型来耗尽小鼠发育的特定阶段的Nap1l1，并分析染色质的组成。该项目有望揭示组蛋白伴侣蛋白Nap1l1的功能，以及该蛋白在发育过程中如何影响染色质重组。更好地了解组蛋白伴侣蛋白及其在重编程和分化过程中如何调节染色质结构，将有助于开发再生医学的新应用。

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.