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.