| Literature DB >> 33986176 |
Marlies P Rossmann1,2, Karen Hoi1,2, Victoria Chan1,2, Brian J Abraham3, Song Yang2, James Mullahoo4, Malvina Papanastasiou4, Ying Wang5, Ilaria Elia6, Julie R Perlin2, Elliott J Hagedorn2, Sara Hetzel7, Raha Weigert7, Sejal Vyas6, Partha P Nag4, Lucas B Sullivan8, Curtis R Warren9, Bilguujin Dorjsuren1,2, Eugenia Custo Greig1,2, Isaac Adatto1,2, Chad A Cowan9, Stuart L Schreiber4, Richard A Young3,10, Alexander Meissner1,4,7, Marcia C Haigis6, Siegfried Hekimi5, Steven A Carr4, Leonard I Zon11,2.
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.Entities:
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Year: 2021 PMID： 33986176 PMCID： PMC8177078 DOI： 10.1126/science.aaz2740
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728