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Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis.
Rossmann, Marlies P; Hoi, Karen; Chan, Victoria; Abraham, Brian J; Yang, Song; Mullahoo, James; Papanastasiou, Malvina; Wang, Ying; Elia, Ilaria; Perlin, 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.
Affiliation
  • Rossmann MP; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Hoi K; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Chan V; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Abraham BJ; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Yang S; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Mullahoo J; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Papanastasiou M; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • Wang Y; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Elia I; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Perlin JR; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Hagedorn EJ; Department of Biology, McGill University, Montréal, Québec H3A 1B1, Canada.
  • Hetzel S; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Weigert R; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Vyas S; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Nag PP; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • Sullivan LB; Department of Genome Regulation, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • Warren CR; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Dorjsuren B; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Greig EC; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Adatto I; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Cowan CA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Schreiber SL; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Young RA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Meissner A; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Haigis MC; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
  • Hekimi S; Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Carr SA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Zon LI; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Science ; 372(6543): 716-721, 2021 05 14.
Article in En | MEDLINE | ID: mdl-33986176
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Transcription, Genetic / Zebrafish Proteins / Erythropoiesis / Mitochondria Type of study: Prognostic_studies Limits: Animals Language: En Journal: Science Year: 2021 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Transcription Factors / Transcription, Genetic / Zebrafish Proteins / Erythropoiesis / Mitochondria Type of study: Prognostic_studies Limits: Animals Language: En Journal: Science Year: 2021 Type: Article Affiliation country: United States