Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis
Name
nihms-1707328.pdf
Description
Accepted version
Size
1.43 MB
Format
Adobe PDF
Checksum (MD5)
34651a7e2818b32f369f7076f126488a
Author(s)
Rossmann, Marlies P
Hoi, Karen
Chan, Victoria
Abraham, Brian J
Yang, Song
Mullahoo, James
Papanastasiou, Malvina
Wang, Ying
Elia, Ilaria
Perlin, Julie R
Date Issued
2021
Journal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
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.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/science.aaz2740
