HMGA2 Maintains Hematopoietic Stem Cell Via Pleiotropic Regulation of the Transcription in Stress Conditions

High-mobility group AT-hook 2 (Hmga2), an epigenetic modifier, opens the chromatin and modulate the transcription. Hmga2 is highly expressed in fetal and adult hematopoietic stem cells (HSCs). Hmga2 over-expression has been shown to promote self-renewal of HSC, however the molecular mechanism of how Hmga2 enhanced the self-renewal of HSC is still unclear. In this study, we assessed the function of Hmga2 in HSCs in steady and stress conditions by utilizing new Hmga2 conditional knock-in (KI) mouse and Hmga2 conditional knock-out mouse, which were crossed with either Cre-ERT2 mouse or Vav1-iCre mouse. Hmga2 KI mice showed a mild elevation in platelet counts, but did not develop malignancies in one year observation period. We performed a competitive transplantation assay by using purified HSCs, and found that wild-type HSCs diminished the repopulating capacity at the tertiary transplantation, Hmga2 KI HSCs maintained higher chimerism in myeloid cells and platelets in the PB and HSCs in the BM. We found that Hmga2 KO cells reduced the repopulating capacity, compared to wild-type cells. Thus, the expression of Hmga2 is critical for the self-renewal of HSC upon the transplantation. By performing RNA-sequencing of HSCs in homeostatic condition, we found that Hmga2 KI HSCs showed positive enrichments in cell cycle and proliferative signature, but maintained a stem cell signature, compared to wild-type HSCs. Since Hmga2 has been shown to globally open the chromatin in neural stem cells, we performed ATAC-sequence analysis in HSCs. Notably, Hmga2 KI HSCs showed 539 opened and 387 closed chromatin in H3K27ac-marked active regulatory regions, compared to wild-type HSCs. Among these opened genes by Hmga2, we generated a virus vector for fifteen genes, which were highly expressed in Hmga2 KI HSCs, and found that ectopic expression of Igf2bp2, an RNA binding protein, increased self-renewal capacity of HSC, but did not induce the enhanced production of myeloid cells and platelets that were observed in Hmga2 KI cells, in in vitro and in vivo settings. Indeed, Hmga2-ChIP-sequencing revealed that Hmga2 was directly bound to a proximal region of the Igf2bp2 gene, and CRISPR/Cas9-mediated deletion of the Igf2bp2 gene canceled the enhanced self-renewal capacity of Hmga2 KI HSCs, indicating that the Hmga2-Igf2bp2 axis is critical for the self-renewal of HSC.