Hepatocyte nuclear factor 4α (HNF4α) is a dimeric transcription factor that controls as much as 60% of all liver genes. However, how it achieves such broad functional diversity is unknown. Here, we show that inflammation and immune pathway genes are differentially regulated in an isoform-dependent manner, confirming that each isoform homodimer preferentially regulates a subset of HNF4α targets. With all 12 human HNF4α isoform clones, we tested combinatorial pairings to determine whether isoform heterodimers are functional. Indeed, synergistic and potent pairing combinations of isoform heterodimers were noted for HNF4α3-8, HNF4α6-12, and HNF4α5-8 that activated CYP7A1, IL6, and IL17A genes, respectively. Surprisingly, these genes are not at all activated by their corresponding isoform homodimers, suggesting that a particular heterodimer pair can regulate its own subset of target genes. Given the combinatorial possibility of 66 isoform heterodimers, our data provide the basis for a more detailed understanding of the diverse influence of HNF4α.

肝细胞核因子4α（HNF4α）是一种二聚体转录因子，可控制多达60％的所有肝基因。但是，如何实现如此广泛的功能多样性尚不得而知。在这里，我们显示炎症和免疫途径基因以同工型依赖性方式被不同地调节，证实每个同工型同二聚体优先调节HNF4α靶标的一个子集。对于所有12个人类HNF4α同工型克隆，我们测试了组合配对，以确定同工型异二聚体是否具有功能。确实，对于激活CYP7A1，IL6和IL17A的HNF4α3-8，HNF4α6-12和HNF4α5-8，注意到同工型异二聚体的协同和有效配对组合基因分别。令人惊讶的是，这些基因根本没有被其相应的同工型同二聚体激活，表明特定的异二聚体对可以调节其自身的靶基因子集。考虑到66种同工型异二聚体的组合可能性，我们的数据为更详细地了解HNF4α的不同影响提供了基础。