학술논문
Cell-specific transcriptional control of mitochondrial metabolism by TIFl[gamma] drives erythropoiesis
Document Type
Academic Journal
Author
Rossmann, Marlies P.; Hoi, Karen; Chan, Victoria; Abraham, Brian J.; Yang, Song; Mullahoo, James; Papanastasiou, Malvina; Wang, Ying; Elia, Maria; Periin, Julie R.; Hagedorn, Elliott J.; Hetzel, Sara; Weigert, Raha; Vyas, Sejal; Nag, Partha P.; Sullivan, Lucas B.; Warren, Curtis R.; Dorjsuren, Bilguujin; Greig, Eugenia Custo; Adatto, Isaac; Cowan, Chad A.; Schreiber, Stuart L.; Young, Richard A.; Meissner, Alexander; Haigis, Marcia C.; Hekimi, Siegfried; Carr, Steven A.; Zon, Leonard I.
Source
Science. May 14, 2021, Vol. 372 Issue 6543, p716, 6 p.
Subject
Language
English
ISSN
0036-8075
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 (tifly). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIFly directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tifly loss, CoQ levels are reduced, and a high succinate/a-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.