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.