Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver

Abstract

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

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

“…Indeed, HNF4A was recently shown to support epithelial regeneration in the intestine in response to irradiation in a mouse genetic model [ 66 ]. Moreover, HNF4A is required for termination of liver regeneration, which requires inhibition of hepatocyte proliferation and reacquisition of their fully differentiated phenotype [ 67 , 68 , 69 ]. Accordingly, HNF4A is necessary to maintain hepatocyte identity in adult mice through regulation of liver-specific genes involved in lipid, glucose, and xenobiotic metabolism, as well as blood coagulation [ 67 , 70 , 71 ].…”

“…The crucial roles of HNF4 in the control of cell identity and function of endodermal organs are exerted in tight collaboration with additional TFs. HNF4 functionally connects with these TFs at different levels including cross regulation of their gene expression and, as described in greater details in the following section, collaborative binding to and regulation of non-TF cell identity genes important for tissue homeostasis and function [ 69 , 88 , 89 ]. Indeed, expression of HNF4 is coordinately controlled with that of other cell-specific TFs through extensive auto- and cross-regulatory loops [ 37 , 90 ] that define the typical organization of cell-specific TF networks [ 6 , 91 ].…”

“…These multiple regulatory interactions within the hepatic TF networks contribute to the high expression levels of the individual TFs [ 92 ]. In line with super-enhancers (i.e., a set of clustered enhancers displaying exceptionally strong indicators of activity such as chromatin opening, active histone marks or TF recruitment) being linked to highly expressed genes required for the establishment and maintenance of cell identity [ 93 ], HNF4A was identified as a core TF in super-enhancer-associated networks in human and mouse liver [ 69 , 90 ]. In addition to ensuring high expression of the individual TFs, such gene network organization confers stability of expression, rendering the network more robust against environmental insults which may transiently affect expression or activity of a single TF, as indirectly shown by HNF4A deletion at different stages of hepatocyte differentiation [ 92 ].…”

“…Modulation of HNF4 signaling through changes in expression or chromatin binding is not restricted to fluctuating physiological circumstances such as those linked to feeding but also occurs in pathophysiological situations. For instance, partial hepatectomy (PHx) of the mouse liver is accompanied by reduced chromatin accessibility as well as H3K27ac levels at HNF4A binding sites, decreased HNF4A genome occupancy, and diminished expression of HNF4A itself [ 68 , 69 ]. In line, reduced HNF4A expression and binding were identified as major contributors to the suppression of hepatocyte-specific genes and downregulation of liver biosynthetic functions during the liver repopulation process after acute injury in the Fumarylacetoacetate hydrolase ( Fah ) null mouse model [ 125 ].…”

“…In line, reduced HNF4A expression and binding were identified as major contributors to the suppression of hepatocyte-specific genes and downregulation of liver biosynthetic functions during the liver repopulation process after acute injury in the Fumarylacetoacetate hydrolase ( Fah ) null mouse model [ 125 ]. Decreased HNF4A expression, subsequently leading to the collapse of the TF networks controlling identity, has been observed in additional murine models of acute liver damage including sepsis and drug-induced acute liver injury resulting from the administration of a single high dose of acetaminophen or carbon tetrachloride (CCl4) [ 69 , 90 ]. HNF4A loss upon acute injury also occurs in the intestine, with both HNF4A expression and chromatin binding being suppressed in a mouse model of acute colitis [ 84 , 126 ].…”