5.1 HNF4α1(P1a-α1) protein partners
P1a-α1 represents the isoform for which most studies have been carried out to identify transcriptional coregulators. This is probably because this isoform was the first to be characterized to contain both AF-1 and AF-2 transactivation domains, making it a strong candidate to extrapolate for similar interactions in the context of the other isoforms and their capacity to recruit the polymerase II. For example, It was observed that during initial steps of transcription preinitiation complex assembly, P1a-α1 binds to Transcription factor II B (TFIIB) and allow its interaction with TATA-binding protein (TBP) with the help of both AF-1 and AF-2 transactivation domains (Figure 2) [55]. On the other hand, both AF-1 and AF-2 can interact with the CREB binding protein (CBP), which in turn acetylates P1a-α1 isoform to prevent its export to the cytoplasm and increase its affinity and stabilize its interaction with DNA [56]. While the interaction between CBP and the AF-1 domain reduces the overall potential in its transcriptional activation [57], AF-1 presence is indispensable for bridging these two proteins and confers a greater affinity for the transcriptional complex as opposed to other isoforms such as P2a-α7, which is devoid of this domain [26, 58]. It was also reported that the Nuclear Receptor Coactivator (NCOA) 1 directly associates with the AF-2 domain of P1a-α1 both in vivo [11] and in vitro [26] (Figure 2). Their co-expression led to the activation of HNF1α in the HepG2 hepatoma cell line associated with the regulation of glucose homeostasis [11]. To this end, it was found that the transcriptional activity of P1a-α1 was increased by its combination with NCOA1, NCOA2, p160, and p300 [11, 58]. Although synergistic studies involving NCOA3 and the above-mentioned proteins including P1a-α1 has not been thoroughly investigated, NCOA3 was shown interacting with P1a-α1 [59, 60]. P1a-α1 also interacts via its AF-2 domain with Receptor interacting domain 2 (RID2) of the Nuclear Receptor Corepressor (NCOR) 2. This interaction abolishes transcriptional activation mediated by the cofactors CBP, NCOA2 and p300 by competing for the same host region of these coactivators [61]. Furthermore, it has been observed that the presence of the AF-1 domain potentiates the repression effect of NCOR2 (Figure 2); this could explain why the P1a-α1 isoform is recruited when there is an interaction between NCOR2 and histone deacetylase (HDAC) 3 [58]. Similar findings were reported for corepressors such as small heterodimer partner (SHP) [60] and small heterodimer partner interacting leucine zipper protein (SMILE) [62]. However, the nature of the mechanisms that trigger these interactions are not entirely clear.