Non-redundant functions of H2A.Z.1 and H2A.Z.2 in chromosome segregation and cell cycle progression

H2A.Z is a H2A-type histone variant essential for many aspects of cell biology, ranging from gene expression to genome stability. From deuterostomes, H2A.Z evolved into two paralogues, H2A.Z.1 and H2A.Z.2, that differ by only three amino acids and are encoded by different genes (H2AFZ and H2AFV, respectively). Despite the importance of this histone variant in development and cellular homeostasis, very little is known about the individual functions of each paralogue in mammals. Here, we have investigated the distinct roles of the two paralogues in cell cycle regulation and unveiled non-redundant functions for H2A.Z.1 and H2A.Z.2 in cell division. Our findings show that H2A.Z.1 regulates the expression of cell cycle genes such as Myc and Ki-67 and its depletion leads to a G1 arrest and cellular senescence. On the contrary, H2A.Z.2, in a transcription independent manner, is essential for centromere integrity and sister chromatid cohesion regulation, thus playing a key role in chromosome segregation. 3 samples were analysed: 1) Control si; 2) H2A.Z.1 si and 3) H2A.Z.2 si

H2A.Z是一类H2A型组蛋白变体（histone variant），在从基因表达调控到基因组稳定性维持的诸多细胞生物学过程中发挥不可或缺的作用。在后口动物（deuterostomes）中，H2A.Z演化出两个旁系同源基因（paralogues），即H2A.Z.1与H2A.Z.2；二者仅在3个氨基酸位点存在差异，分别由基因H2AFZ与H2AFV编码。尽管该组蛋白变体在发育进程与细胞稳态维持中具有重要意义，但目前对于哺乳动物中两种旁系同源基因各自的功能仍知之甚少。本研究针对两种旁系同源基因在细胞周期调控中的独特功能展开探究，揭示了H2A.Z.1与H2A.Z.2在细胞分裂过程中发挥的非冗余功能。研究结果显示，H2A.Z.1可调控Myc与Ki-67等细胞周期相关基因的表达，其敲降会导致细胞G1期阻滞与细胞衰老。与之相反，H2A.Z.2则以转录非依赖的方式，对维持着丝粒完整性与姐妹染色单体黏连调控至关重要，从而在染色体分离过程中发挥关键作用。本研究共分析了3组样本：1）Control si组；2）H2A.Z.1 si组；3）H2A.Z.2 si组。