Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 01238, USA.
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.
Science. 2021 May 14;372(6543):716-721. doi: 10.1126/science.aaz2740.
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 mutant embryos defective for transcriptional intermediary factor 1 gamma (). 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 loss, CoQ levels are reduced, and a high succinate/α-ketoglutarate ratio leads to increased histone methylation. A CoQ analog rescues '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.
转录和代谢都会影响细胞功能，但专门针对调节细胞命运的代谢途径的转录控制很少被定义。我们使用化学抑制剂筛选发现，嘧啶生物合成酶二氢乳清酸脱氢酶 (DHODH) 的抑制作用可以挽救无血液斑马鱼突变体胚胎中红细胞分化缺陷，该突变体胚胎中缺乏转录中间因子 1 伽马 ()。这种挽救依赖于 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。当 缺失时，CoQ 水平降低，而高琥珀酸/α-酮戊二酸比导致组蛋白甲基化增加。CoQ 类似物可以挽救无血液表型。这些结果表明，线粒体代谢是谱系转录因子的关键输出物，它在早期血液谱系中驱动细胞命运决定。
