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.

转录和代谢都影响细胞功能，但很少定义调节细胞命运的代谢途径的专门转录控制。我们发现，使用化学抑制筛选，抑制嘧啶生物合成酶二氢乳清酸脱氢酶 (DHODH) 可挽救无血斑马鱼月光 (mon)突变胚胎中转录中间因子 1 γ ( tif1γ ) 缺陷的红系分化。这种拯救取决于 DHODH 与线粒体呼吸的功能联系。转录延伸因子 TIF1γ 直接控制辅酶 Q (CoQ) 合成基因的表达。在tif1γ损失，辅酶Q水平降低，高琥珀酸/α-酮戊二酸比例导致组蛋白甲基化增加。辅酶 Q 类似物拯救了mon的无血表型。这些结果表明，线粒体代谢是一种谱系转录因子的关键输出，它驱动早期血液谱系中的细胞命运决定。