The histone acetyltransferase KAT6B is required for hematopoietic stem cell development and function.

IF 5.9 2区医学 Q1 CELL & TISSUE ENGINEERING Stem Cell Reports Pub Date : 2024-04-09 Epub Date: 2024-03-21 DOI:10.1016/j.stemcr.2024.02.005

Maria I Bergamasco, Nishika Ranathunga, Waruni Abeysekera, Connie S N Li-Wai-Suen, Alexandra L Garnham, Simon N Willis, Helen M McRae, Yuqing Yang, Angela D'Amico, Ladina Di Rago, Stephen Wilcox, Stephen L Nutt, Warren S Alexander, Gordon K Smyth, Anne K Voss, Tim Thomas

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Abstract

The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing hematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined the role of KAT6B in the hematopoietic system. We found that KAT6B sustained the fetal hematopoietic stem cell pool but did not affect viability or differentiation. KAT6B was essential for normal levels of histone H3 lysine 9 (H3K9) acetylation but not for a previously proposed target, H3K23. Compound heterozygosity of Kat6b and the closely related gene, Kat6a, abolished hematopoietic reconstitution after transplantation. KAT6B and KAT6A cooperatively promoted transcription of genes regulating hematopoiesis, including the Hoxa cluster, Pbx1, Meis1, Gata family, Erg, and Flt3. In conclusion, we identified the hematopoietic processes requiring Kat6b and showed that KAT6B and KAT6A synergistically promoted HSC development, function, and transcription. Our findings are pertinent to current clinical trials testing KAT6A/B inhibitors as cancer therapeutics.

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组蛋白乙酰转移酶KAT6B是造血干细胞发育和功能所必需的。

组蛋白赖氨酸乙酰转移酶 KAT6B（MYST4、MORF、QKF）是导致预后不良的血液恶性肿瘤的染色体反复易位的靶点。利用 Kat6b 基因缺失和小鼠过表达，我们确定了 KAT6B 在造血系统中的作用。我们发现，KAT6B能维持胎儿造血干细胞池，但不影响其活力或分化。KAT6B对组蛋白H3赖氨酸9（H3K9）乙酰化的正常水平至关重要，但对之前提出的目标H3K23却不是。Kat6b和与之密切相关的基因Kat6a的复合杂合性会导致移植后的造血功能丧失。KAT6B 和 KAT6A 能协同促进调节造血的基因转录，包括 Hoxa 簇、Pbx1、Meis1、Gata 家族、Erg 和 Flt3。总之，我们确定了需要 Kat6b 的造血过程，并表明 KAT6B 和 KAT6A 能协同促进造血干细胞的发育、功能和转录。我们的发现与目前测试 KAT6A/B 抑制剂作为癌症疗法的临床试验有关。

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来源期刊

Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY

CiteScore

10.50

自引率

1.70%

发文量

200

审稿时长

28 weeks

期刊介绍： Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.