PUBLICATION

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

Authors
Rossmann, M.P., Hoi, K., Chan, V., Abraham, B.J., Yang, S., Mullahoo, J., Papanastasiou, M., Wang, Y., Elia, I., Perlin, J.R., Hagedorn, E.J., Hetzel, S., Weigert, R., Vyas, S., Nag, P.P., Sullivan, L.B., Warren, C.R., Dorjsuren, B., Greig, E.C., Adatto, I., Cowan, C.A., Schreiber, S.L., Young, R.A., Meissner, A., Haigis, M.C., Hekimi, S., Carr, S.A., Zon, L.I.
ID
ZDB-PUB-210515-3
Date
2021
Source
Science (New York, N.Y.)   372: 716-721 (Journal)
Registered Authors
Adatto, Isaac, Zon, Leonard I.
Keywords
none
Datasets
GEO:GSE163453, GEO:GSE163454, GEO:GSE136456, GEO:GSE163483
MeSH Terms
  • Animals
  • Citric Acid Cycle
  • DNA Methylation
  • Electron Transport
  • Embryo, Nonmammalian/metabolism
  • Enzyme Inhibitors/pharmacology
  • Erythropoiesis*
  • Gene Expression Regulation
  • Histones/metabolism
  • Leflunomide/pharmacology
  • Metabolic Networks and Pathways
  • Methylation
  • Mitochondria/metabolism*
  • Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors
  • Oxygen Consumption
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Transcription, Genetic*
  • Ubiquinone/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
33986176 Full text @ Science
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping