RNA Group, Département de microbiologie et d'infectiologie, Faculté de médecine et sciences de la santé, Université de Sherbrooke and Centre de recherche du CHUS, Sherbrooke, QC, Canada.
CNRS UMR8246, Université Pierre et Marie Curie, 75005, Paris, France.
Cell Death Dis. 2018 Jan 22;9(2):70. doi: 10.1038/s41419-017-0115-3.
TAF6δ is a pro-apoptotic splice variant of the RNA polymerase II general transcription factor, TAF6, that can dictate life vs. death decisions in animal cells. TAF6δ stands out from classical pro-apoptotic proteins because it is encoded by a gene that is essential at the cellular level, and because it functions as a component of the basal transcription machinery. TAF6δ has been shown to modulate the transcriptome landscape, but it is not known if changes in gene expression trigger apoptosis nor which TAF6δ-regulated genes contribute to cell death. Here we used microarrays to interrogate the genome-wide impact of TAF6δ on transcriptome dynamics at temporal resolution. The results revealed changes in pro-apoptotic BH3-only mitochondrial genes that correlate tightly with the onset of cell death. These results prompted us to test and validate a role for the mitochondrial pathway by showing that TAF6δ expression causes cytochrome c release into the cytoplasm. To further dissect the mechanism by which TAF6δ drives apoptosis, we pinpointed BIM and NOXA as candidate effectors. siRNA experiments showed that both BIM and NOXA contribute to TAF6δ-dependent cell death. Our results identify mitochondrial effectors of TAF6δ-driven apoptosis, thereby providing the first of mechanistic framework underlying the atypical TAF6δ apoptotic pathway's capacity to intersect with the classically defined apoptotic machinery to trigger cell death.
TAF6δ 是 RNA 聚合酶 II 一般转录因子 TAF6 的促凋亡剪接变体，可在动物细胞中决定生死决策。TAF6δ 与经典的促凋亡蛋白不同，因为它是由一个在细胞水平上必不可少的基因编码的，并且因为它作为基本转录机制的一部分发挥作用。TAF6δ 已被证明可以调节转录组景观，但尚不清楚基因表达的变化是否引发细胞凋亡，也不知道哪些 TAF6δ 调节的基因有助于细胞死亡。在这里，我们使用微阵列在时间分辨率上探究 TAF6δ 对转录组动力学的全基因组影响。结果显示，促凋亡 BH3 仅线粒体基因的变化与细胞死亡的发生密切相关。这些结果促使我们通过显示 TAF6δ 表达导致细胞色素 c 释放到细胞质中来测试和验证线粒体途径的作用。为了进一步剖析 TAF6δ 驱动细胞凋亡的机制，我们确定了 BIM 和 NOXA 作为候选效应物。siRNA 实验表明，BIM 和 NOXA 均有助于 TAF6δ 依赖性细胞死亡。我们的结果确定了 TAF6δ 驱动凋亡的线粒体效应物，从而为 TAF6δ 凋亡途径的非典型能力与经典定义的凋亡机制交叉以引发细胞死亡提供了第一个机制框架。
