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.