Nuclear IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming

Although, IDH1 has been recognized to play critical roles in the regulation of dynamic chromatin states, the mechanism remained largely unknown. Here, using the human erythropoiesis system, we presented an innovative perspective of metabolism independent role of nuclear IDH1. We discovered that IDH1 acted as a nuclear located chromatin-binding protein. Knockdown of IDH1 induced chromatin reorganization and subsequently aroused aberrant biological events germination on erythroid precursors in a metabolism independent manner. IDH1 knockdown induced genome-wide coordinate changes in the distribution and intensity of multiple histone marks, among which H3K79me3 was identified to be the decisive factor in chromatin state reprogramming. Integrating ChIP-seq, ATAC-seq and RNA-seq recognized SIRT1 to be the key gene affected by IDH1 deficiency. Taken together, these findings provided a novel insight for further clarifying the fundamental biological function of IDH1 which had substantial implications for an in-depth understanding of the pathogenesis of diseases with IDH1 dysfunction and accordingly the development of therapeutic strategies.