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Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.

Josepmaria Argemi 1 Maria U Latasa 2 Stephen R Atkinson 3 Ilya O Blokhin 4 Veronica Massey 5 Joel P Gue 1 Joaquin Cabezas 5 Juan J Lozano 6 Derek van Booven 4 Aaron Bell 7 Sheng Cao 8 Lawrence A Vernetti 1 Juan P Arab 8 Meritxell Ventura-Cots 1 Lia R Edmunds 1 Constantino Fondevilla 9 Peter Stärkel 10 Laurent Dubuquoy 11 Alexandre Louvet 11 Gemma Odena 5 Juan L Gomez 1 Tomas Aragon 2 Jose Altamirano 12 Juan Caballeria 6 Michael J Jurczak 1 D Lansing Taylor 1 Carmen Berasain 2 Claes Wahlestedt 4 Satdarshan P Monga 7 Marsha Y Morgan 13 Pau Sancho-Bru 14 Philippe Mathurin 11 Shinji Furuya 15 Carolin Lackner 16 Ivan Rusyn 15 Vijay H Shah 8 Mark R Thursz 3 Jelena Mann 17 Matias A Avila 2 Ramon Bataller 5
1 PITT - University of Pittsburgh
2 UNAV - Universidad de Navarra [Pamplona]
3 Imperial College London
4 UMMSM - University of Miami Leonard M. Miller School of Medicine
5 UNC - University of North Carolina [Chapel Hill]
6 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
7 University of Pittsburgh School of Medicine
8 Mayo Clinic [Rochester]
9 University of Barcelona
10 UCL - Université Catholique de Louvain = Catholic University of Louvain
11 LIRIC - Lille Inflammation Research International Center - U 995
12 Vall d'Hebron University Hospital [Barcelona]
13 UCL - University College of London [London]
14 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
15 Texas A&M University [College Station]
16 Medical University Graz
17 Newcastle University [Newcastle]
Abstract : 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.
Keywords : 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
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https://hal.univ-lille.fr/hal-03113100
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Soumis le : lundi 18 janvier 2021 - 09:58:44
Dernière modification le : mercredi 3 novembre 2021 - 05:13:51

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Josepmaria Argemi, Maria U Latasa, Stephen R Atkinson, Ilya O Blokhin, Veronica Massey, et al.. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.. Nature Communications, Nature Publishing Group, 2019, Nature Communications, 10 (1), pp.3126. ⟨10.1038/s41467-019-11004-3⟩. ⟨hal-03113100⟩

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