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.