TAF4 promotes pre-initiation complex formation and HNF4A occupancy of regulatory elements required to activation post-natal gene expression programme in hepatocytes (RNA-seq)

The nuclear receptor HNF4A regulates embryonic and post-natal hepatocyte gene expression. Using hepatocyte-specific inactivation in mice, we show that the TAF4 subunit of TFIID acts as a cofactor for HNF4A in vivo and that HNF4A interacts directly with the TAF4-TAF12 heterodimer in vitro. In vivo, TAF4 is required to maintain HNF4A-directed embryonic gene expression at post-natal stages and for HNF4A-directed activation of post-natal gene expression. TAF4 promotes HNF4A occupancy of functional cis-regulatory elements located adjacent to the transcription start sites of post-natal expressed genes and for pre-initiation complex formation required for their expression. Promoter-proximal HNF4A-TFIID interactions are therefore required for pre-initiation complex formation and stable HNF4A occupancy of regulatory elements as two concomitant mutually dependent processes. RNA profiles in wild-type and Taf4-/- livers by deep sequencing核受体家族的肝细胞核因子4α (HNF4A) 可调控胚胎期与出生后肝细胞的基因表达。本研究借助小鼠肝细胞特异性失活模型，证实通用转录因子IID (transcription factor IID, TFIID) 的TAF4亚基在体内可作为HNF4A的辅因子，且HNF4A在体外可直接与TAF4-TAF12异二聚体相互结合。体内实验显示，TAF4是维持出生后阶段HNF4A介导的胚胎基因表达，以及介导HNF4A激活出生后基因表达所必需的。TAF4可促进HNF4A结合于出生后表达基因转录起始位点附近的功能性顺式调控元件，并促进其表达所需的预起始复合物 (pre-initiation complex, PIC) 的组装。因此，启动子近端的HNF4A-TFIID相互作用作为两个相互伴随且互为依赖的过程，对于预起始复合物组装以及HNF4A稳定结合调控元件均不可或缺。本研究通过深度测序分析了野生型与Taf4基因敲除 (Taf4-/-) 小鼠肝脏的RNA表达谱。