Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.
Résumé
Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.
Mots clés
Adult
Aged
Animals
Biopsy
Chromatin Assembly and Disassembly
DNA Methylation
Disease Progression
Epigenesis
Genetic
Female
Gene Expression Profiling
Gene Expression Regulation
Hepatitis
Alcoholic
Hepatocyte Nuclear Factor 4
Hepatocytes
Humans
Liver
Male
Middle Aged
Polymorphism
Sequence Analysis
RNA
Transforming Growth Factor beta1
Domaines
Sciences du Vivant [q-bio]
Origine : Fichiers produits par l'(les) auteur(s)
