KDM6A, a histone demethylase, regulates stress hematopoiesis and early B-cell differentiation

•Lack of Kdm6a affects female but not male hematopoiesis.•Lack of KDM6A does not alter global levels of H3K27 methylation, its presumed target, and might thus function independently of histone demethylation.•KDM6A is essential for the regulation of stress hematopoiesis.•Absence of KDM6A affects primarily B-cell differentiation, which is initiated at the level of HSPCs. Histone methylases and demethylases regulate gene expression programs in hematopoiesis. The molecular function of the demethylase KDM6A in normal hematopoiesis and, in particular, for the hematopoietic stem and progenitor cell (HSPC) compartment remains only partially understood. Female but not male Kdm6a–/– HSPCs were functionally impaired in adoptive transfer experiments as well as upon proliferative stress induced by 5-fluorouracil. Loss of Kdm6a affected primarily early B cells and erythroid and myeloid progenitor cells with respect to both number and function. Global gene expression analyses revealed a shared altered gene signature in Kdm6a–/– pro-B and pre-B cells that is also present in HSPCs, supporting that altered B-cell differentiation in Kdm6a–/– animals is already initiated in HSPCs. Interestingly, loss of KDM6A did not affect the global level of methylation of H3K27, its presumed target, in hematopoietic cells. Our data indicate a critical role for KDM6A in the regulation of hematopoietic differentiation and differentiation-specific gene expression programs, with a prominent role in early B-cell differentiation that is likely independent of H3K27 methylation status.