The acidic domain and its linker region of Hmga2 is critical for driving the self-renewal of 2 hematopoietic stem cell

High mobility group AT-hook 2 (HMGA2) is a chromatin modifier protein critical for fetal development and leukemia propagation through its binding to chromatin and DNA via its AT-hook domains; however, the molecular mechanism by which Hmga2 activates expression of target genes to drive the self-renewal capacity of hematopoietic stem cell (HSC) remains unclear. We generated a Rosa26 locus Hmga2 conditional knock-in mice revealing that over-expression of Hmga2 significantly promotes the self-renew of HSCs that maintain their fitness in the bone marrow, thereby is not sufficient to initiate malignant diseases in mice, consistent with previous studies indicating that Hmga2 is a proto-oncogene. By assessing the cellular function of Hmga2 mutants lacking the functional domains, we demonstrated that the first AT-hook, C-terminus acidic domain and its linker region in Hmga2 are critical for activating genes involved in stem cell signature such as Igf2bp2 gene to drive the proliferation of HSCs. Conversely, over-expression of Hmga1, a member of the HMGA family, which differ in the linker region, did not drive the proliferation of HSCs. Thus, this study underlines a potential role of the acidic domain and its linker region in Hmga2 for modulating the transcription and the self-renewal function of HSC.