The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

中文翻译：

---

组蛋白赖氨酸乙酰转移酶 HBO1 (KAT7) 调节造血干细胞的静止和自我更新。


组蛋白乙酰转移酶 HBO1（MYST2、KAT7）对于原肠胚形成后发育、组蛋白 H3 赖氨酸 14 乙酰化 (H3K14Ac) 和胚胎模式基因的表达是不可或缺的。在本研究中，我们报道了 HBO1 在调节成人造血中造血干细胞功能中的作用。我们使用 2 个互补的 cre 重组酶转基因有条件地删除 Hbo1（Mx1-Cre 和 Rosa26-CreERT2）。 Hbo1 缺失小鼠在 Hbo1 缺失后 2 至 6 周因造血衰竭、血液和骨髓全血细胞减少而濒临死亡。在竞争性移植实验中，Hbo1 缺失的骨髓细胞未能在接受血液消融的受体中重新繁殖。 Hbo1 缺失导致造血祖细胞迅速丧失。红细胞、骨髓细胞、B 细胞和 T 细胞谱系的谱系限制祖细胞数量减少。 HBO1 的缺失导致静态造血干细胞（HSC）以异常高的速度进入细胞周期。循环的 HSC 以自我更新为代价产生祖细胞，这导致 HSC 库耗尽。从机制上讲，Hbo1缺失后，对HSC功能重要的基因在富含HSC的细胞群中下调，包括对HSC静止和自我更新至关重要的基因，如Mpl、Tek(Tie-2)、Gfi1b、Egr1、Tal1(Scl)、 Gata2、Erg、Pbx1、Meis1 和 Hox9，以及对多能祖细胞和谱系特异性祖细胞重要的基因，例如 Gata1。 HBO1 是 H3K14Ac 在整个基因组中所必需的，特别是在 HSC 静止和自我更新所需的基因位点上。我们的数据表明，HBO1 促进成人造血过程中 HSC 维持和自我更新所必需的转录因子网络的表达。