The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal

• Published in: Blood Vol. 139; no. 6; pp. 845 - 858
• Main Authors: Yang, Yuqing, Kueh, Andrew J., Grant, Zoe L., Abeysekera, Waruni, Garnham, Alexandra L., Wilcox, Stephen, Hyland, Craig D., Di Rago, Ladina, Metcalf, Don, Alexander, Warren S., Coultas, Leigh, Smyth, Gordon K., Voss, Anne K., Thomas, Tim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.02.2022
• Subjects: Animals; Cell Self Renewal; Cells, Cultured; Cellular Senescence; Gene Deletion; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Mice; Mice, Inbred C57BL
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021013954

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. •In the absence of HBO1, H3K14ac is lost, and hematopoietic stem cells differentiate into progenitors at the expense of self-renewal.•HBO1 governs stem cell quiescence and self-renewal by promoting gene transcription, including Gata2, Mpl, Erg, Pbx1, Meis1, and Hoxa9. [Display omitted]