Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver.
Animals
Basic-Leucine Zipper Transcription Factors
/ genetics
Cell Cycle Proteins
/ genetics
Cell Line
Cells, Cultured
Chemical and Drug Induced Liver Injury
/ genetics
Chromatin Immunoprecipitation Sequencing
Down-Regulation
Endoplasmic Reticulum Stress
/ drug effects
Gene Expression Profiling
Gene Expression Regulation
/ genetics
Gene Regulatory Networks
Hepatocytes
/ drug effects
Humans
Liver Diseases
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nuclear Proteins
/ genetics
Thapsigargin
/ toxicity
Transcription Factors
/ genetics
Transcriptome
/ genetics
Up-Regulation
NFIL3
PAR-bZIP
liver injury
sepsis
super-enhancer
Journal
Molecular systems biology
ISSN: 1744-4292
Titre abrégé: Mol Syst Biol
Pays: England
ID NLM: 101235389
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
05
08
2019
revised:
09
04
2020
accepted:
14
04
2020
entrez:
15
5
2020
pubmed:
15
5
2020
medline:
1
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32407006
doi: 10.15252/msb.20199156
pmc: PMC7224309
doi:
Substances chimiques
BRD4 protein, human
0
Basic-Leucine Zipper Transcription Factors
0
Brd4 protein, mouse
0
Cell Cycle Proteins
0
NFIL3 protein, human
0
Nfil3 protein, mouse
0
Nuclear Proteins
0
Transcription Factors
0
Thapsigargin
67526-95-8
Banques de données
GEO
['GSE122613', 'GSE122508']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9156Subventions
Organisme : NCI NIH HHS
ID : R01 CA251698
Pays : United States
Informations de copyright
©2020 The Authors. Published under the terms of the CC BY 4.0 license.
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