7. Conclusions and future perspectives
Since its initial discovery more than three decades ago, HNF4α has been extensively studied in the context of regulating gene transcription, metabolism, and tissue differentiation. Subsequent structural analyses of the HNF4A locus revealed a high level of complexity, with the significant finding that HNF4α no longer refers to one single protein but englobes different classes of isoforms produced mainly by the usage of two different promoters and alternative splicing. As highlighted above, recent advances have supported specific roles attributed to each HNF4α P1 and P2 subgroup, at least in gut epithelial tissues where several isoforms from both subgroups are detected. Additionally, some reports have identified coactivators and corepressors interacting with HNF4α isoforms. Some of these studies considered the specificity of each single isoforms in their experimental design, with the conclusion that some of these interactions depend on the specific nature of these isoforms. Although there is a broad agreement on the importance of several identified HNF4α copartners and their function in regulating gene transcription, the specific nature of these interactions among various isoforms and their biological impact awaits to be addressed. Even though recent advances highlighted the interactome nature of these HNF4α isoforms, more studies are needed to further dissect at both mechanistic and biological levels the differences between all these isoforms. The assessment of whether these interactions occur directly between identified proteins and their specific HNF4α isoforms is critical to inform their global biological role further.
On the other hand, there is common knowledge on the specificity of gene promoter usage in the production and localization of HNF4α P1 and P2 isoforms subclasses among various tissues. However, the exact distribution of every HNF4α isoform of these subclasses during pathophysiological processes is not well established. One of the main reasons to explain this lack of knowledge comes from the difficulty of raising specific antibodies for every single isoform since none harbor their own unique protein domains. Given the central role of HNF4α in the maintenance of several tissues and diseases, one of the future challenges will be to distinguish the contribution of each of the HNF4α isoforms to this end. These strategies will become particularly attractive for the development of therapeutical targeting interventions.