GSE176103
The mitochondrial metabolic enzyme Hexokinase 2 regulates stem cell function and differentiation by increasing chromatin openness and the accessibility of stem cell genes [RNA-Seq]
Mitochondrial metabolites regulate the function and differentiation of leukemic and normal stem cells by affecting epigenetic marks.  However, it is less understood how mitochondrial enzymes localize to the nucleus to control stem cell function. We discovered that the mitochondrial metabolic enzyme Hexokinase 2 (HK2) localizes to the nucleus in leukemic and normal hematopoietic stem cells. Overexpression of nuclear HK2 increased leukemic stem cell (LSC) properties and decreased differentiation while selective knockdown of nuclear HK2 promoted differentiation and decreased stem cell function. The nuclear localization of HK2 was phosphorylation dependent and required active import and export. Nuclear HK2 regulated LSC and differentiation independent of its enzymatic and metabolic activity. HK2 interacted with nuclear proteins that regulate chromatin openness and increased chromatin accessibilities at sites associated with the LSC+ signature and DNA damage repair. Consistent with these effects, nuclear HK2 increased repair of DNA damage and contributed to the mechanism by which LSCs resist DNA damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes regulate gene expression and stem cell function independent of their metabolic function. Overall design: Gene expression analysis upon knock-down of Nuclear HK2.