Citation

Rossmann MP, Hoi K, Chan V, Abraham BJ, Yang S, Mullahoo J, Papanastasiou M, Wang Y, Elia I, Perlin JR, Hagedorn EJ, Hetzel S, Weigert R, Vyas S, Nag PP, Sullivan LB, Warren CR, Dorjsuren B, Greig EC, Adatto I, Cowan CA, Schreiber SL, Young RA, Meissner A, Haigis MC, Hekimi S, Carr SA, Zon LI. 2021. Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis. Science (New York, N.Y.). 372(6543):716-721. Pubmed: 33986176 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 mutant embryos defective for transcriptional intermediary factor 1 gamma (). 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 loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues '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.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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Photo of Len Zon

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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