Data from: TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

The functions of the TAF subunits of mammalian TFIID in physiological processes remain poorly characterised. Here we describe a novel function of TAFs in directing genomic occupancy of a transcriptional activator. Using liver-specific inactivation in mice, we show that the TAF4 subunit of TFIID is required for post-natal hepatocyte maturation. TAF4 promotes pre-initiation complex (PIC) formation at post-natal expressed liver function genes and down-regulates a subset of embryonic expressed genes by increased RNA polymerase II pausing. The TAF4-TAF12 heterodimer interacts directly with HNF4A and in vivo TAF4 is necessary to maintain HNF4A-directed embryonic gene expression at post-natal stages and promotes HNF4A occupancy of functional cis-regulatory elements adjacent to the transcription start sites of post-natal expressed genes. Stable HNF4A occupancy of these regulatory elements requires TAF4-dependent PIC formation highlighting that these are mutually dependent events. Local promoter-proximal HNF4A-TFIID interactions therefore act as instructive signals for post-natal hepatocyte differentiation.

哺乳动物转录因子IID（Transcription Factor IID, TFIID）的TBP相关因子（TBP-associated factors, TAF）亚基在生理过程中的功能仍未得到充分解析。本研究揭示了TAF的一项全新功能：调控转录激活因子的基因组结合定位。通过在小鼠中实施肝脏特异性基因失活策略，我们证实转录因子IID的TAF4亚基是出生后肝细胞成熟所必需的。TAF4可促进出生后表达的肝脏功能基因处的预起始复合物（Pre-initiation Complex, PIC）组装，并通过增强RNA聚合酶II暂停来下调部分胚胎期表达的基因。TAF4-TAF12异二聚体可直接与肝细胞核因子4α（Hepatocyte Nuclear Factor 4 Alpha, HNF4A）相互作用；在体内，TAF4是维持出生后阶段HNF4A调控的胚胎期基因表达所必需的，并可促进HNF4A结合至出生后表达基因的转录起始位点（transcription start sites, TSS）附近的功能性顺式调控元件。这些调控元件的稳定HNF4A结合依赖于TAF4介导的预起始复合物组装，这表明二者存在相互依赖的调控关系。因此，启动子近端的局部HNF4A-TFIID相互作用可作为出生后肝细胞分化的指导性信号。