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POSTPONED: Cell-specific transcriptional regulation of mitochondrial metabolism by TIF1γ drives erythropoiesis

Date:13.03.2020, 11:00 - 12:00
Speaker: Dr. Marlies Rossmann, Harvard University
Location: CRTD, ground floor, auditorium left
Host: Prof. Michael Brand



Transcription and metabolism both influence cell function yet it has rarely been defined how transcriptional control regulates dedicated metabolic pathways to govern cell fate. My manuscript shows that a metabolic program directly instructed by a lineage transcription factor is required for embryonic erythroid differentiation. Zebrafish moonshine (mon) mutant embryos defective for the conserved transcriptional intermediary factor 1 gamma (tif1γ) lack red blood cells (RBCs) due to a transcription elongation block. To uncover dysregulated pathways in mon mutants, I performed a chemical suppressor screen with 3,120 compounds. Among the hits, I identified several inhibitors of dihydroorotate dehydrogenase (DHODH), an essential enzyme for pyrimidine synthesis. Leflunomide as well as the structurally unrelated DHODH inhibitor brequinar rescue the formation of primitive erythroid cells in the mon mutant. DHODH needs to be inhibited in mon embryos during gastrulation to achieve its rescue – at around a time when the first blood progenitors are born. In agreement with this, I showed in blastula transplants that tif1γ, in addition to its cell-autonomous role, plays a role in the hematopoietic niche for RBC development. Importantly, Leflunomide’s ability to rescue blood formation in mon mutants depends on mitochondrial coenzyme Q (CoQ) activity to which DHODH is functionally linked across the mitochondrial membrane. In-vivo metabolomics analysis revealed that tif1γ loss results in mitochondrial respiration defects. Through genome-wide transcriptome and chromatin immunoprecipitation analyses, I found that genes encoding CoQ metabolic enzymes are direct TIF1γ targets. Strikingly, treatment with the CoQ analog decylubiquinone results in rescue of βe3 globin expression in mon embryos. My work highlights how a lineage transcription factor tunes energy metabolism to set the stage for erythroid cell fate, which could have parallels also in the emergence and differentiation of other tissue lineages.

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