4. HNF4α isoforms and their action on gene expression
Most of the HNF4α isoforms play an essential role in transcriptional
regulation, mainly through activation and, to a lesser extent,
repression of many genes involved in various biological processes. For
example, P1a-α1 was found to enhance the transcription of the human
androstane receptor (hCAR) gene promoter in human liver cells, whereas
P2a-α7 acted as a repressor in this context [49]. One additional
pioneer study specifically addressed the potential differential impact
of two different P1 and P2 HNF4α isoforms at a larger scale by measuring
the transcriptomic impact of forced expression of either P1a-α2 or
P2a-α8 in a human intestinal epithelial cell line originally devoid of
HNF4α expression [50]. It was concluded that P1a-α2 influenced a set
of genes linked to the inhibition of cell growth and death. In contrast,
P2a-α8 specifically influenced genes involved in the progression of the
cell cycle and development [50]. In a following study, Lambertet al . investigated the impact of every single HNF4α isoform on
global transcriptomic changes in the same human intestinal epithelial
cell line [31]. This analysis indicated that both P1a-α1 and P1a-α2
were the most potent isoforms to influence the transcriptome, while P2
isoforms were less efficient overall. Interestingly, the non-canonical
P1 isoforms (P1b-α4, P1b-α5, and P1b-α6) did not significantly impact
gene expression, possibly because of their incapacity to physically
interact with the classical HNF4α element [31]. P2a-α9 was found to
act mainly as a repressor of gene expression, while both P2b-α10 and
P1-α3 mainly exerted a positive action on gene expression. These
observations collectively suggested that the presence of the A/B domain,
rather than the repressive F domain, was the main criterion to explain
these differences. HNF4α isoforms with a shorter F domain were primarily
ineffective in influencing gene expression, suggesting that this domain
can play a crucial role during transcriptional regulation [31]. An
additional study investigated the combinatory impact of these isoforms
on the expression of a subset of genes involved in inflammation and
immune response [32]. Again, a specific regulatory pattern of gene
expression was observed depending on the nature of these isoforms in
this context. For example, the combination of P1a-α2 and P1a-α3 or
P2a-α9 and P2b-α12 as heterodimers was more efficient in repressing
specific target genes than their homodimer counterparts. On the other
side, P1a-α3 and P2a-α8 or P1b-α6 and P2b-α12 heterodimers were found
more potent in transcriptional activation again when compared to their
homodimers equivalent. One concrete example is the cytochrome P450
family 7 subfamily A member 1 (CYP7A1), an enzyme involved in
cholesterol metabolism, that was found specifically upregulated with
P1a-α3 and P2a-α8 heterodimers [32]. Still, several mechanistical
aspects relative to the specificity of action of these various isoforms,
including the specific nature of assembled proteins in the composition
of HNF4α transcriptional complexes for a given gene, remain to be
further explored.