IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming in a metabolic enzyme independent manner

Abstract

Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that was involved in the modulation of cellular metabolism, epigenetic modification and redox states homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be tightly associated with the pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains to be further explored. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We showed that knockdown of IDH1 induced chromatin reorganization and subsequently led to abnormalities of various key biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of -ketoglutarate (-KG). We further revealed that deficiency of IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies. Key PointsO_LIIDH1 deficiency impaired terminal erythropoiesis; C_LIO_LIIDH1 deficiency leads to chromatin states reprogramming by causing aberrant accumulation and genome-wide re-distribution of H3K79me3; C_LIO_LIDyserythropoiesis is caused by upregulation of SIRT1 induced by H3K79me3 accumulation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/599556v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@328986org.highwire.dtl.DTLVardef@1e2e8a0org.highwire.dtl.DTLVardef@166885org.highwire.dtl.DTLVardef@1283261_HPS_FORMAT_FIGEXP M_FIG C_FIG