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 (tif1g). This rescue depends on the functional link of DHODH to mitochondrial respiration. The transcription elongation factor TIF1g directly controls coenzyme Q (CoQ) synthesis gene expression. Upon tif1g loss, CoQ levels are reduced, and a high succinate/a-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. [ABSTRACT FROM AUTHOR]