Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

Abstract

Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor family whose expression and activities are restricted to a limited number of organs including the liver and gastrointestinal tract. In this review, we present robust evidence pointing to HNF4 as a master regulator of cellular differentiation during development and a safekeeper of acquired cell identity in adult organs. Importantly, we discuss that transient loss of HNF4 may represent a protective mechanism upon acute organ injury, while prolonged impairment of HNF4 activities could contribute to organ dysfunction. In this context, we describe in detail mechanisms involved in the pathophysiological control of cell identity by HNF4, including how HNF4 works as part of cell-specific TF networks and how its expression/activities are disrupted in injured organs.

Keywords: HNF4 nuclear receptor; cell identity; functional genomics; liver and gastrointestinal pathophysiology.

Figure 1

Mechanisms involved in the control of cell identity by HNF4. Intrinsic control of HNF4 activities through isoform heterodimers, post-translational modifications (PTMs), and potential ligands add up to the modulation of its functions through involvement in cell-specific transcription factor (TF) networks. Combinatorial control of cell identity by HNF4 and additional cell identity by TFs consist of 2 interdependent layers where these TFs modulate each other’s expression and coordinately regulate common (non-TF) cell identity target genes.

Figure 2

Proposed relationship between strength and duration of organ insults and HNF4-mediated control of cell identity. Acute injury triggers loss of HNF4 transcriptional activity through decreased expression and/or chromatin recruitment, with the degree of the inhibition correlating with the severity of the insult. HNF4 loss is accompanied by a shutdown of cell identity, partly attributable to a collapse of the TF networks controlling identity gene expression. This loss is transient (i.e., expression of HNF4 and other identity TFs is re-established once the stress resolves) and seems to be a protective mechanism to cope with the acute insult in the context of reallocation of transcriptional resources. However, when the insult persists leading to chronic stress/injury, repression of HNF4 and cell identity endures, which might precipitate accompanying organ dysfunction and occurrence of cancer.