2. HNF4α isoforms are produced from 2 independent P1 and P2 promoters
HNF4α was originally isolated and purified from rat liver nuclear extracts and characterized as a factor that binds to specific promoter elements of the transthyretin (TTR ) and apolipoprotein C2 genes [24]. Like other members of the nuclear receptor family, HNF4α was originally described as containing an A/B domain including an AF-1 transactivation region, which allows interaction with different proteins involved in regulating transcription; a C domain or DNA-binding domain (DBD) containing specific recognition elements that bind to promoter regions of their target genes; a D domain that acts as a hinge between the C and E domains; an E domain capable of interacting with a ligand binding domain (LBD) and that contains an AF-2 ligand-dependent activation region; and an F domain with repressive functions of protein activity [25, 26] (Figure 1A). HNF4A gene is located on chromosome 20 [27], more precisely on the long arm between regions 12 and 13 [28]. A critical feature of HNF4Α is the presence of P1 and P2, two independent promoters that can drive gene transcription and are separated by more than 45 kb [29]. By alternative splicing, these promoters can give rise to a total of 12 isoforms which, accordingly to the promoter driving their expression, have been classified into two subgroups of isoforms called P1 (α1 to α6) and P2 (α7 to α12) [30, 31] (Figure 1B). P1 (α1 to α3) and P2 (α7 to α9) isoforms have been extensively studied and characterized in various organs and tissues. They are referred to as the canonical isoforms, as opposed to the non-canonical P1 (α4 to α6) and P2 (α10 to α12) isoforms for which little is known about their distribution and functions [31].