Epigenetics and Metabolic Control of Hematopoiesis and Leukemia
How epigenetics and metabolism cooperate to control normal development and disease processes is a fundamentally important question with significant clinical implication. Many epigenetic enzymes catalyzing DNA or histone modifications are susceptible to changes in co-substrates of cellular metabolism, but little is known about whether and how altered epigenetics influences metabolism during cancer progression.
We recently described that inactivation of the histone methyltransferase EZH2 promotes leukemic transformation by aberrant activation of branched-chain amino acid (BCAA) metabolism in leukemia-initiating cells, establishing a new molecular link between altered epigenetics and metabolism in cancer progression (Gu et al., 2019). This study was among the first to show that epigenetic alterations rewire intracellular metabolism during cancer transformation, causing epigenetic and metabolic vulnerabilities in cancer-initiating cells.
In other studies, we compared the proteomic and transcriptomic changes in human primary hematopoietic stem/progenitor cells and erythroid cells, and uncovered pathways related to mitochondrial biogenesis enhanced through protein translation, establishing a new mechanism for post-transcriptional control of mitochondria related to hematologic defects in mitochondrial diseases and aging (Liu et al., 2017).
Building on these findings, we are examining the epigenetic and metabolic liabilities of blood stem cells in development and pathological conditions. Ongoing studies include:
- BCAA metabolism in stem cell function and cancer development
- Metabolic control of normal and pathological erythropoiesis
- Crosstalk between epigenetic gene regulation and intracellular metabolism in hematopoiesis and leukemia