Hepatocyte nuclear factor 4α multiple isoforms, their functions, and their interactomes

Abstract

Hepatocyte nuclear factor 4-alpha (HNF4α) is a master regulator gene belonging to the nuclear receptor superfamily and is involved in regulating a wide range of critical biological processes in different organs. Structurally, the HNF4A locus is organized into two independent promoters and is subjected to alternative splicing to produce twelve distinct isoforms. However, little is known about the biological impact of each isoform and the mechanisms by which they regulate transcription. Proteomic analyses have led to the identification of proteins that interact with specific HNF4α isoforms. The identification and validation of these interactions and their roles in the co-regulation of targeted gene expression are essential to better understand the role of this transcription factor in different biological processes and pathologies. This review addresses the discoveries of different HNF4α isoforms and the main functions of the P1 and P2 isoform subgroups. It also provides information on the most recent focus areas in research on the nature and function of proteins associated with each of the isoforms in some biological contexts.

Dynamic RNA polymerase II occupancy drives differentiation of the intestine under the direction of HNF4

“…HNF4 transcription factors have roles in activating enhancer chromatin and are essential for the expression of vital villus-enriched genes. 44 - 46 Nevertheless, the influence of HNF4 on the dynamics of Pol II remains uncertain, specifically regarding its influence on Pol II occupancy and the subsequent implications for its role as a pro-differentiation factor. To study this, we leveraged a previously generated mouse model that integrates the Villin-Cre ERT2 transgenic allele 47 with Hnf4a flox/flox 48 on an Hnf4g −/− background 44 (hereafter referred to as HNF4αγ DKO ) ( Figure 5A ).…”

Dynamic RNA Polymerase II Recruitment Drives Differentiation of the Intestine under the direction of HNF4

“…HNF4 transcription factors interact with chromatin remodeling and chromatin looping proteins and are required for Pol II recruitment to differentiation genes HNF4 transcription factors have roles in activating enhancer chromatin and are essential for the expression of vital villus-enriched genes. [38][39][40] Nevertheless, the influence of HNF4 on the dynamics of Pol II remains uncertain, specifically regarding its influence on Pol II recruitment and the subsequent implications for its role as a prodifferentiation factor. To study this, we leveraged a previously generated mouse model which integrates the Villin-Cre ERT2 transgenic allele 41 with Hnf4a flox/flox 42 on a Hnf4g -/background 38 (hereafter referred to as Hnf4αγ DKO) (Fig.…”