Hoxa5 is preferentially expressed in haematopoietic stem cells (HSCs) and multipotent progenitor cells (MPPs), and is more highly expressed in expanding HSCs. To date, little is known regarding the role of Hoxa5 in HSCs and downstream progenitor cells in vivo. In this study, we show that increased expression of Hoxa5 in haematopoietic stem cells leads to aberrant erythropoiesis in vivo. Hoxa5 differentially modifies the cell cycle of HSCs and lineage committed progenitor cells, depending on the cellular context. Hoxa5 drives HSCs, but not MPPs, through the cell cycle and arrests erythroid progenitor cells in G0 phase. Although the HSC pool shrinks after overexpression of Hoxa5, HSCs sustain the abilities of self-renewal and multipotency. In vivo, Hoxa5 has two effects on erythropoiesis: it causes a predominance of mature erythroid lineage cells and the partial apoptosis of erythroid progenitors. RNA-seq indicates that multiple biological processes, including erythrocyte homeostasis, cell metabolism, and apoptosis, are modified by Hoxa5. The results of this study indicate that Hoxa5 is a key regulator of the HSC cell cycle, and the inappropriate expression of Hoxa5 in lineage-committed progenitor cells leads to aberrant erythropoiesis.
Keywords: BFU-E, burst-forming unit-erythroid; CFU-G, colony forming unit-granulocyte; CFU-GM, colony forming unit-granulocyte macrophage; CMP, common myeloid progenitor; GMP, granulocyte monocyte progenitor; HSC, haematopoietic stem cell; LSK, lineage negative, Sca1 positive, cKit positive; MEP, megakaryocyte-erythroid progenitor; MP, myeloid progenitor; MPP, multipotent progenitor; apoptosis; cell cycle; erythropoiesis; haematopoietic stem cells, Hoxa5.