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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE136452 | GEO | 2021/06/09

REPOSITORIES: GEO

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Transcriptionally regulated energy metabolism drives early erythropoiesis (mon RNA-seq)

Project description:Transcription and metabolism both influence cell function yet dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. Through a chemical suppressor screen, we discovered that inhibition of the pyrimidine biosynthesis enzyme DHODH rescues erythroid differentiation in bloodless moonshine mutant embryos defective for the transcription elongation factor tif1γ. This rescue depends on the functional link of DHODH to mitochondrial respiration. Low α-ketoglutarate levels caused by tif1γ loss lead to histone hypermethylation. TIFγ directly controls coenzyme Q synthesis gene expression and coenzyme Q levels are reduced in moonshine mutants. A coenzyme Q analogue rescues moonshine’s bloodless phenotype. These results demonstrate mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.

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