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Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis
Science ( IF 44.7 ) Pub Date : 2021-05-14 , DOI: 10.1126/science.aaz2740
Marlies P Rossmann 1, 2 , Karen Hoi 1, 2 , Victoria Chan 1, 2 , Brian J Abraham 3 , Song Yang 2 , James Mullahoo 4 , Malvina Papanastasiou 4 , Ying Wang 5 , Ilaria Elia 6 , Julie R Perlin 2 , Elliott J Hagedorn 2 , Sara Hetzel 7 , Raha Weigert 7 , Sejal Vyas 6 , Partha P Nag 4 , Lucas B Sullivan 8 , Curtis R Warren 9 , Bilguujin Dorjsuren 1, 2 , Eugenia Custo Greig 1, 2 , Isaac Adatto 1, 2 , Chad A Cowan 9 , Stuart L Schreiber 4 , Richard A Young 3, 10 , Alexander Meissner 1, 4, 7 , Marcia C Haigis 6 , Siegfried Hekimi 5 , Steven A Carr 4 , Leonard I Zon 1, 2
Affiliation  

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.



中文翻译:

TIF1γ对线粒体代谢的细胞特异性转录控制驱动红细胞生成

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。

更新日期:2021-05-14
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