BioProject

Hematopoietic stem cell (HSC) respond to various stresses and produce mature blood cells; however, it is not clear how HSCs maintain and restore hematopoiesis by determining their self-renewal and differentiation fates. More...

Hematopoietic stem cell (HSC) respond to various stresses and produce mature blood cells; however, it is not clear how HSCs maintain and restore hematopoiesis by determining their self-renewal and differentiation fates. High mobility group AT-hook 2 (Hmga2) is a chromatin modifier protein that is highly expressed in HSCs and regulates transcription of target genes. In steady state, Hmga2 knock-out (KO) mice and Hmga2-over-expressing conditional knock-in (KI) mice both did not show a significant change in hematopoiesis; however, in response to 5-FU injection, Hmga2 KI mice showed enhanced self-renewal of HSCs and rapid hematopoietic recovery increasing platelet counts, while Hmga2 KO mice decreased numbers of HSCs and megakaryocyte progenitor cells and delayed hematopoietic recovery. Because the expression of Hmga2 was able to repress transcription of inflammatory response genes, we assessed Hmga2-binding regions and chromatin accessibility in HSCs post the in vivo injection of 5-FU or in vitro treatment with TNF-a. We found that Hmga2 bound to distinct regions and reduced chromatin accessibility in inflammatory response genes, resulting in the reduced expression of these genes in the stress condition. As the acidic domain in the Hmga2 protein was phosphorylated by Casein kinase 2, the inhibition of phosphorylation in the acidic domain by substitution with alanine resulted in impairments in the stress-induced chromatin binding of Hmga2 and the expansion of HSCs after the stress insults. Thus, Hmga2 dynamically modulated the chromatin accessibility and transcription of genes in HSC via phosphorylation of the Hmga2 protein and protected HSC in stress hematopoiesis. Less...