Abstract
HNF4α is a master regulator gene belonging to the nuclear receptor
superfamily involved in regulating a wide range of critical biological
processes in different organs. Structurally, the HNF4A locus is
organized with two independent promoters and is subjected to alternative
splicing with the production of twelve distinct isoforms. Little is
known about the mechanisms each isoform uses to regulate transcription
and their biological impact, with some reports addressing these aspects.
Proteomic analyses have led to identifying proteins that interact with
specific HNF4α isoforms. The identification and validation of these
interactions and their role in co-regulating targeted gene expression
are essential to understand better the role of this transcription factor
in different biological processes and pathologies. This review addresses
the historical origin of HNF4α isoforms, some of the main functions of
the P1 and P2 isoform subgroups and provide information on the most
recent hot topic research on the nature and function of proteins
associated with each of the isoforms in some biological contexts.
Introduction
Hepatocyte nuclear factor 4-alpha (HNF4α) is a master transcription
factor part of the nuclear receptor superfamily and is primarily
conserved during evolution [1, 2]. HNF4α was initially isolated and
purified from the liver in the 1990s, and since its discovery, numerous
studies have supported the vital role of this protein in development.
One of the first pieces of evidence to this end came from its disruption
in an engineered mouse knockout model in which deleted individuals did
not survive beyond E9 of embryonic development [2]. It was further
concluded that HNF4α was crucial for primary endoderm, liver, pancreas,
and gut epithelia development [3]. After birth, HNF4α continues to
be expressed in these organs, and its expression is maintained in both
murine [4, 5] and human [6] adult tissues. Several independent
research groups have collectively confirmed the crucial role of HNF4α in
liver gluconeogenesis, glycogen synthesis, tissue architecture,
epithelial morphogenesis, hepatocyte differentiation, lipid metabolism,
and detoxification of xenobiotic agents [7-9]. In the pancreas,
HNF4α was also shown to control insulin production by promoting gene
promoter activation [10] and glucose-induced insulin secretion
[11, 12]. It was also discovered that mutations in the HNF4Agene are responsible for maturity-onset diabetes of the young subtype 1
(MODY1) [13-15]. In the stomach, HNF4α is detected in the pit,
isthmus, neck, and pepsinogen-secreting zymogenic
cells of the gastric corpus. Deletion of Hnf4a in the mouse
gastric epithelium led to increased epithelial proliferation while
interfering with zymogenic cell differentiation [16]. In the large
mouse intestine, loss of HNF4α during embryonic development interferes
with crypt formation and goblet cell maturation and reduces epithelial
cell proliferation with an impact on external muscle and vascular tissue
reduction [17]. In the mouse adult intestine, HNF4α primarily acts
as an activator of gene transcription. Its deletion negatively impacts
polysaccharides and acid mucopolysaccharides production, mucins, and
aquaporins gene expression and increases intestinal permeability
[18]. Its deletion also negatively impacts expression of ion
transport genes and stimulates epithelial apoptosis and mucosal immune
cells infiltration [19].
All these observations support a predominant role of HNF4α during
developmental organogenesis and organ function maintenance. Deregulation
of HNF4α transcriptional activity is associated with several
pathologies, including liver cirrhosis, hepatocellular carcinoma, MODY1,
colitis, and colon cancer [20].
Alternative splicing can generate functional protein isoforms or
alloforms for multiple human genes [21]. HNF4Α can produce a
total of 12 isoforms for which some of these were previously shown to
harbor specific biological functions [22, 23]. However, the
biological role of each of these isoforms in the different processes in
which HNF4α is involved remains to be discovered, mainly because most of
past work focused on some isoforms with the assumption that they were
functionally equivalent. Large-scale identification of specific protein
interactome for each HNF4α isoform remains crucial to distinguish the
specific nature of targeted genes and their associated biological
functions according to the physio-pathological state dependent on HNF4α
[22, 23].This review will focus on the work done so far to identify
interactions of specific HNF4α isoforms with protein components involved
in transcriptional regulation and their impact on specific gene
expression and biological functions.