美国哈佛大学干细胞与再生生物学系Leonard I. Zon研究组取得最新进展。他们发现TIF1γ对线粒体代谢的细胞特异性转录控制驱动红细胞生成。相关论文于2021年5月14日发表在《科学》杂志上。

他们使用化学抑制剂筛选发现，对嘧啶生物合成酶二氢乳清酸脱氢酶（DHODH）的抑制可挽救无转录能力的转录中介因子1γ（tif1γ）缺陷的无血斑马鱼月光（mon）突变体胚胎中的类红素分化。这种挽救取决于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。

tif1γ丢失后，CoQ值降低，琥珀酸/α-酮戊二酸比例高会导致组蛋白甲基化增加。CoQ类似物可挽救mon的无血表型。这些结果表明线粒体代谢是谱系转录因子的关键输出，该谱系转录因子驱动早期血统中的细胞命运决定。

据介绍，转录和代谢都影响细胞功能，但是很少定义调节细胞命运的代谢途径的专门转录控制。

附：英文原文

Title: Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Author: Marlies P. Rossmann, Karen Hoi, Victoria Chan, Brian J. Abraham, Song Yang, James Mullahoo, Malvina Papanastasiou, Ying Wang, Ilaria Elia, Julie R. Perlin, Elliott J. Hagedorn, Sara Hetzel, Raha Weigert, Sejal Vyas, Partha P. Nag, Lucas B. Sullivan, Curtis R. Warren, Bilguujin Dorjsuren, Eugenia Custo Greig, Isaac Adatto, Chad A. Cowan, Stuart L. Schreiber, Richard A. Young, Alexander Meissner, Marcia C. Haigis, Siegfried Hekimi, Steven A. Carr, Leonard I. Zon

Issue&Volume: 2021/05/14

Abstract: 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.

DOI: 10.1126/science.aaz2740

Source: https://science.sciencemag.org/content/372/6543/716