ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration

In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5‐fluorouracil‐induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCR high ) were enriched within the stem cell fraction at the expense of more proliferative EPCR Low HSCs. These EPCR High HSCs were initially more primitive than EPCR Low HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis‐regulatory elements in progenitor cell‐related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY‐dependent histone acetylation promoted differentiation into CD48 + progenitor cells. Collectively, these results indicate that the dynamic control of ACLY‐dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration. Synopsis The metabolic mechanisms driving hematopoietic stem cell (HSC) activation and recovery of the blood system after myeloablation remain unclear. This study reports ATP citrate lyase (ACLY)‐dependent histone acetylation and changes in chromatin accessibility as dynamic determinants of HSC function during bone marrow regeneration. HSC gene expression, metabolic status and histone acetylation differ between early and late stages post 5‐FU treatment in mice. Early after 5‐FU treatment, increased mitochondrial membrane potential, ACLY expression and global H3K27ac levels enhance HSC expansion and in vivo engraftment potential. Increased HSC differentiation capacity at late post‐5‐FU stages is associated with increased accessibility of progenitor cell‐related genes. Suppression of ACLY‐mediated metabolism maintains HSC identity during late regeneration. Graphical Abstract ACLY‐dependent coupling of metabolic state and chromatin accessibility facilitates recovery of the blood system after myeloablation.