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

Argemi, Josepmaria ; Latasa, Maria U ; Atkinson, Stephen R ; Blokhin, Ilya O ; Massey, Veronica ; Gue, Joel P ; Cabezas, Joaquin ; Lozano, Juan J ; Van Booven, Derek ; Bell, Aaron ; Cao, Sheng ; Vernetti, Lawrence A ; Arab, Juan P ; Ventura-Cots, Meritxell ; Edmunds, Lia R ; Fondevila, Constantino ; Stärkel, Peter ; Dubuquoy, Laurent ; Louvet, Alexandre ; Odena, Gemma ; Gomez, Juan L ; Aragon, Tomas ; Altamirano, Jose ; Caballeria, Juan ; Jurczak, Michael J ; Taylor, D Lansing ; Berasain, Carmen ; Wahlestedt, Claes ; Monga, Satdarshan P ; Morgan, Marsha Y ; Sancho-Bru, Pau ; Mathurin, Philippe ; Furuya, Shinji ; Lackner, Carolin ; Rusyn, Ivan ; Shah, Vijay H ; Thursz, Mark R ; Mann, Jelena ; Avila, Matias A ; Bataller, Ramon

Nature communications, 2019-07, Vol.10 (1), p.3126-19, Article 3126 [Peer Reviewed Journal]

England: Nature Publishing Group

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Title:
Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Author: Argemi, Josepmaria ; Latasa, Maria U ; Atkinson, Stephen R ; Blokhin, Ilya O ; Massey, Veronica ; Gue, Joel P ; Cabezas, Joaquin ; Lozano, Juan J ; Van Booven, Derek ; Bell, Aaron ; Cao, Sheng ; Vernetti, Lawrence A ; Arab, Juan P ; Ventura-Cots, Meritxell ; Edmunds, Lia R ; Fondevila, Constantino ; Stärkel, Peter ; Dubuquoy, Laurent ; Louvet, Alexandre ; Odena, Gemma ; Gomez, Juan L ; Aragon, Tomas ; Altamirano, Jose ; Caballeria, Juan ; Jurczak, Michael J ; Taylor, D Lansing ; Berasain, Carmen ; Wahlestedt, Claes ; Monga, Satdarshan P ; Morgan, Marsha Y ; Sancho-Bru, Pau ; Mathurin, Philippe ; Furuya, Shinji ; Lackner, Carolin ; Rusyn, Ivan ; Shah, Vijay H ; Thursz, Mark R ; Mann, Jelena ; Avila, Matias A ; Bataller, Ramon
Subjects: Adult ; Aged ; Alcoholic beverages ; Animal models ; Animals ; Biopsy ; Chromatin Assembly and Disassembly ; Chromatin remodeling ; Deoxyribonucleic acid ; Disease Progression ; DNA ; DNA Methylation ; Epigenesis, Genetic ; Epigenetics ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation ; Gene polymorphism ; Gene sequencing ; Hepatitis ; Hepatitis, Alcoholic - genetics ; Hepatitis, Alcoholic - pathology ; Hepatocyte nuclear factor 4 ; Hepatocyte Nuclear Factor 4 - genetics ; Hepatocyte Nuclear Factor 4 - metabolism ; Hepatocytes ; Hepatocytes - pathology ; Humans ; Life Sciences ; Liver ; Liver - cytology ; Liver - pathology ; Liver diseases ; Male ; Middle Aged ; Phenotypes ; Polymorphism, Genetic ; Ribonucleic acid ; RNA ; Sequence Analysis, RNA ; Transcription factors ; Transcriptomes ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - metabolism ; Transforming growth factor-b1
Is Part Of: Nature communications, 2019-07, Vol.10 (1), p.3126-19, Article 3126
Description: 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.
Publisher: England: Nature Publishing Group
Language: English;French

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

England: Nature Publishing Group

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