Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Science. 2021 May 14;372(6543):716-721. doi: 10.1126/science.aaz2740.

Abstract

Transcription and metabolism both influence cell function, but dedicated transcriptional control of metabolic pathways that regulate cell fate has rarely been defined. We discovered, using a chemical suppressor screen, that inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) rescues erythroid differentiation in bloodless zebrafish moonshine (mon) mutant embryos defective for transcriptional intermediary factor 1 gamma (tif1γ). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1γ directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1γ loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues mon's bloodless phenotype. These results demonstrate that mitochondrial metabolism is a key output of a lineage transcription factor that drives cell fate decisions in the early blood lineage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Citric Acid Cycle
  • DNA Methylation
  • Electron Transport
  • Embryo, Nonmammalian / metabolism
  • Enzyme Inhibitors / pharmacology
  • Erythropoiesis*
  • Gene Expression Regulation
  • Histones / metabolism
  • Leflunomide / pharmacology
  • Metabolic Networks and Pathways
  • Methylation
  • Mitochondria / metabolism*
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors
  • Oxygen Consumption
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Ubiquinone / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Enzyme Inhibitors
  • Histones
  • Transcription Factors
  • Zebrafish Proteins
  • transcriptional intermediary factor 1gamma, zebrafish
  • Ubiquinone
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase
  • Leflunomide