Lysine acetyltransferase Tip60 is required for hematopoietic stem cells maintenance

Hematopoietic stem cells (HSC) have the potential to replenish the blood system for the lifetime of the organism. Their two defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Here, using conditional gene knockout models, we demonstrate a critical requirement of lysine acetyltransferase 5 (also known as Tip60) for murine HSC maintenance both in the embryonic and adult stages, which depends on its acetyltransferase activity. Genome-wide chromatin and transcriptome profiling revealed that Tip60 co-localizes with c-Myc and that Tip60 deletion suppress the expression of Myc target genes, which are associated with critical biological processes for HSC maintenance, cell-cycle and DNA repair. Notably, acetylated H2A.Z (acH2A.Z) was enriched at the Tip60-bound active chromatin and Tip60 deletion induced a robust reduction in the acH2A.Z / H2A.Z ratio. These results uncover a critical epigenetic regulatory layer for HSC maintenance through Tip60 dependent H2A.Z acetylation to activate Myc target genes.造血干细胞（Hematopoietic stem cells, HSC）具备在生物体整个生命周期中重建造血系统的潜能。其两大标志性特征——自我更新与分化——受到表观遗传调控机制的严格管控。本研究借助条件性基因敲除模型，证实赖氨酸乙酰转移酶5（lysine acetyltransferase 5，亦称为Tip60）对小鼠造血干细胞在胚胎期与成年期的维持均具有关键作用，且该功能依赖其自身的乙酰转移酶活性。全基因组染色质及转录组谱分析显示，Tip60与c-Myc存在共定位现象；Tip60缺失会抑制Myc靶基因的表达，而这些靶基因与造血干细胞维持、细胞周期及DNA修复等核心生物学过程密切相关。值得注意的是，乙酰化组蛋白H2A.Z（acetylated H2A.Z, acH2A.Z）在Tip60结合的活性染色质区域富集；Tip60缺失会显著降低acH2A.Z与H2A.Z的比值。上述研究结果揭示了一条调控造血干细胞维持的关键表观遗传通路：通过Tip60依赖性的H2A.Z乙酰化激活Myc靶基因，进而维持造血干细胞稳态。