3. Specific biological functions of HNF4α P1- and P2-derived
isoforms
Given the complex nature of HNF4α isoforms regulation of expression and
tissue distribution, a few studies have investigated the specific roles
of these isoforms, and with often the limitation of targeting multiple
members contained in either P1 or P2 isoform subgroups. Nevertheless,
important observations were obtained from these studies. Using an exon
swapping strategy, Briancon et al . were able to generate knock-in
mouse models switching the AF-1 activation domain between HNF4α1 (1a-α1)
and HNF4α7 (2a-α7) isoforms driven by P1 or P2 promoters, respectively
[45]. From this strategy, it was found that mice expressing only the
P1 isoform resulted in impaired glucose tolerance. In contrast, those
expressing only the P2 isoform displayed a significant decrease in serum
lipids and steatosis and showed alterations in the transcription of
genes involved in lipid metabolism and transport [45]. When the same
mouse models were used in the context of gut biology, no basal
morphological changes were reported during normal homeostasis of adult
mice [46]. This was not unexpected, given that the conditional
knockout of Hnf4a in intestinal epithelium did not severely
impact this tissue [47]. However, when experimental colitis was
inflicted in these mice, an increase in colitis severity and mortality
was observed in mice expressing P2-only isoform [46]. In the same
report, when cancer-associated colitis was induced among these mouse
models, P1-only isoform individuals exhibited a reduction in intestinal
tumor size and number compared to controls. On the contrary, P2-only
isoform individuals showed a larger and increased number of intestinal
tumors when compared to controls [46]. Although these two previous
studies highlighted some specific biological roles for P1-derived 1a-α1
and P2-derived 2a-α7 isoforms, much needs to be done to picture the
global complexity of whole HNF4α isoforms. In a complementary set of
experiments, Babeu et al . investigated the specific roles of P1
versus P2 groups of isoforms in the human context [48]. P1 subgroup
of isoforms was found to be expressed in association with differentiated
colonocytes, while P2-associated isoforms were preferentially detected
in proliferating colonocytes. This pattern of expression in association
with proliferation versus differentiation cell status was maintained
during colon cancer, with P1 isoforms being repressed and P2 isoforms
induced in the neoplastic tissues compared to their normal margins
[48]. Under these circumstances, the mechanism involved in the
repression of P1 isoforms was found to be dependent on β-catenin
expression [48]. Using a small interfering RNA strategy, the same
report identified specific classes of genes dependent on whole P1 versus
P2 isoforms transcriptional activity [48] . P1-derived isoforms were
involved in regulating genes associated with cell metabolism whereas
P2-derived isoforms were specifically involved in regulating genes
related to cell-cycle progression and survival [48]. Again, although
this study highlighted specific global roles for P1 versus P2 whole
classes of isoforms, further studies are needed to understand the
specific role of every single isoform in these biological contexts.