TATA-binding Associated Factors have distinct roles during early mammalian development

Early embryonic development is a finely orchestrated process that requires precise regulation of gene expression coordinated with morphogenetic events. TATA-box binding protein-associated factors (TAFs), integral components of transcription initiation coactivators like TFIID and SAGA, play a crucial role in this intricate process. Here we show that disruptions in TAF5, TAF12 and TAF13 individually lead to embryonic lethality in the mouse, resulting in overlapping yet distinct phenotypes. Taf5 and Taf12 mutant embryos exhibited a failure to implant post-blastocyst formation, and Taf5 mutants have aberrant lineage specification within the inner cell mass. In contrast, Taf13 mutant embryos successfully implant and form egg-cylinder stages but fail to initiate gastrulation. Strikingly, we observed a depletion of pluripotency factors in TAF13-deficient embryos, including OCT4, NANOG and SOX2, highlighting an indispensable role of TAF13 in maintaining pluripotency. Transcriptomic analysis revealed distinct gene targets affected by the loss of TAF5, TAF12 and TAF13. Thus, we propose that TAF5, TAF12 and TAF13 convey locus specificity to the TFIID complex throughout the mouse genome. Comparative gene expression profiling analysis of RNA-seq data for mouse embryos from a WT, Taf5KO, Taf12KO, or Taf13KO transgenic background.

早期胚胎发育是一项高度协调的精密过程，需要基因表达的精准调控与形态发生事件协同推进。TATA盒结合蛋白相关因子（TATA-box binding protein-associated factors，TAFs）是转录起始共激活因子（如TFIID与SAGA）的核心组成部分，在这一复杂过程中发挥关键作用。本研究显示，TAF5、TAF12与TAF13各自发生功能缺失时，均会导致小鼠胚胎致死，并产生既有重叠又存在差异的表型。Taf5与Taf12突变的胚胎在囊胚形成后无法完成着床，且Taf5突变体的内细胞团内出现了异常的谱系特化。与之相反，Taf13突变的胚胎可顺利着床并形成卵圆柱期，但无法启动原肠运动。值得注意的是，研究人员在TAF13缺陷的胚胎中观察到多能性因子（包括OCT4、NANOG与SOX2）的表达耗竭，这凸显了TAF13在维持多能性过程中不可或缺的作用。转录组学分析显示，TAF5、TAF12与TAF13的功能缺失会影响不同的基因靶标。据此，本研究提出TAF5、TAF12与TAF13可赋予全基因组范围内的TFIID复合物以位点特异性。本研究对野生型（WT）、Taf5基因敲除（Taf5KO）、Taf12基因敲除（Taf12KO）及Taf13基因敲除（Taf13KO）遗传背景下的小鼠胚胎的RNA测序（RNA-seq）数据开展了比较基因表达谱分析。