Transcriptionally regulated energy metabolism drives early erythropoiesis (ChIP-Seq)

Transcription and metabolism both influence cell function but dedicated transcriptional control of metabolic pathways regulating cell fate has rarely been defined. Zebrafish moonshine mutant embryos defective for the transcription elongation factor tif1γ do not make red blood cells. Here, through a chemical suppressor screen we discovered that inhibition of the pyrimidine biosynthesis enzyme DHODH rescues erythroid differentiation in moonshine mutant embryos, which depends on the functional link of DHODH to mitochondrial coenzyme Q activity. In-vivo metabolomics analysis reveals that tif1γ loss results in mitochondrial respiration defects that are associated with reduced expression of genes that encode coenzyme Q synthesis enzymes and are directly bound and controlled by TIF1γ. Treatment of moonshine embryos with a coenzyme Q analogue rescues their bloodless defect. These results demonstrate energy metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage. ChIP-seq analysis of histone 3 lysine 27 acetylation (H3K27Ac), RNA polymerase II (RNA Pol II), RNA polymerase II phosphorylated at Ser2 (RNA Pol II-Ser2P), and TIF1γ in logarithmically growing human HepG2 hepatocellular carcinoma cells.