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Science DOI:10.1126/science.aaz2740

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

Publication TypeJournal Article
Year of Publication2021
AuthorsRossmann, 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, ECusto, Adatto, I, Cowan, CA, Schreiber, SL, Young, RA, Meissner, A, Haigis, MC, Hekimi, S, Carr, SA, Zon, LI
Date Published2021 05 14
KeywordsAnimals, Citric Acid Cycle, DNA Methylation, Electron Transport, Embryo, Nonmammalian, Enzyme Inhibitors, Erythropoiesis, Gene Expression Regulation, Histones, Leflunomide, Metabolic Networks and Pathways, Methylation, Mitochondria, Oxidoreductases Acting on CH-CH Group Donors, Oxygen Consumption, Transcription Factors, Transcription, Genetic, Ubiquinone, Zebrafish, Zebrafish Proteins

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.


Alternate JournalScience
PubMed ID33986176
Grant ListR01 HL048801 / HL / NHLBI NIH HHS / United States
P01 HL032262 / HL / NHLBI NIH HHS / United States
U01 HL134812 / HL / NHLBI NIH HHS / United States
P01 HL131477 / HL / NHLBI NIH HHS / United States
U54 DK110805 / DK / NIDDK NIH HHS / United States
R24 DK092760 / DK / NIDDK NIH HHS / United States
R01 CA213062 / CA / NCI NIH HHS / United States
R35 GM127045 / GM / NIGMS NIH HHS / United States
U54 HG008097 / HG / NHGRI NIH HHS / United States