Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance
Lysine acetyltransferase Tip60 is required for hematopoietic stem cell maintenance
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DOI：
10.1182/blood.2019001279
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发表时间：
2020-10-08
期刊：
影响因子：
20.3
通讯作者：
Tenen, Daniel G.
中科院分区：
文献类型：
--
作者：
Numata, Akihiko;Kwok, Hui Si;Tenen, Daniel G.
造血干细胞（HSC）有潜力在生物体的一生中补充血液系统。它们的两个定义特性，自我更新和分化，受到表观遗传机制的严格调控。使用条件基因敲除模型，我们证明了赖氨酸乙酰转移酶 5（Kat5，也称为 Tip60）对于胚胎和成年阶段小鼠 HSC 维持的关键要求，这取决于其乙酰转移酶活性。小鼠造血干细胞和祖细胞的全基因组染色质和转录组分析表明，Tip60 与 c-Myc 共定位，并且 Tip60 缺失会抑制 Myc 靶基因的表达，而 Myc 靶基因与 HSC 维持、细胞周期和 DNA 修复的关键生物过程相关。值得注意的是，乙酰化 H2A.Z (acH2A.Z) 在 Tip60 结合的活性染色质处富集，Tip60 缺失导致 acH2A.Z/H2A.Z 比率大幅降低。这些结果揭示了 HSC 维持的关键表观遗传调控层，至少部分是通过 Tip60 依赖性 H2A.Z 乙酰化来激活 Myc 靶基因。
Hematopoietic stem cells (HSCs) have the potential to replenish the blood system for the lifetime of the organism. Their 2 defining properties, self-renewal and differentiation, are tightly regulated by the epigenetic machineries. Using conditional gene-knockout models, we demonstrated a critical requirement of lysine acetyltransferase 5 (Kat5, also known as Tip60) for murine HSC maintenance in both the embryonic and adult stages, which depends on its acetyltransferase activity. Genome-wide chromatin and transcriptome profiling in murine hematopoietic stem and progenitor cells revealed that Tip60 colocalizes 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 cycling, 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, at least in part through Tip60-dependent H2A.Z acetylation to activate Myc target genes.