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

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Article number3126
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

hepatitis
Alcoholic Hepatitis
gene expression
Gene expression
Liver
liver
Gene Expression
Epigenomics
Transcription Factors
Hepatocyte Nuclear Factor 4
RNA Sequence Analysis
chromatin
phenotype
animal models
Polymorphism
methylation
Chromatin Assembly and Disassembly
sequencing
regulators
polymorphism

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Argemi, J., Latasa, M. U., Atkinson, S. R., Blokhin, I. O., Massey, V., Gue, J. P., ... Bataller, R. (2019). Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nature communications, 10(1), [3126]. https://doi.org/10.1038/s41467-019-11004-3

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.; Fondevilla, 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 R; 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.

In: Nature communications, Vol. 10, No. 1, 3126, 01.12.2019.

Research output: Contribution to journalArticle

Argemi, J, Latasa, MU, Atkinson, SR, Blokhin, IO, Massey, V, Gue, JP, Cabezas, J, Lozano, JJ, Van Booven, D, Bell, A, Cao, S, Vernetti, LA, Arab, JP, Ventura-Cots, M, Edmunds, LR, Fondevilla, C, Stärkel, P, Dubuquoy, L, Louvet, A, Odena, G, Gomez, JL, Aragon, T, Altamirano, J, Caballeria, J, Jurczak, MJ, Taylor, DL, Berasain, C, Wahlestedt, CR, Monga, SP, Morgan, MY, Sancho-Bru, P, Mathurin, P, Furuya, S, Lackner, C, Rusyn, I, Shah, VH, Thursz, MR, Mann, J, Avila, MA & Bataller, R 2019, 'Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis', Nature communications, vol. 10, no. 1, 3126. https://doi.org/10.1038/s41467-019-11004-3
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. ; Fondevilla, 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 R ; 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. / Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
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AU - Massey, Veronica

AU - Gue, Joel P.

AU - Cabezas, Joaquin

AU - Lozano, Juan J.

AU - Van Booven, Derek

AU - Bell, Aaron

AU - Cao, Sheng

AU - Vernetti, Lawrence A.

AU - Arab, Juan P.

AU - Ventura-Cots, Meritxell

AU - Edmunds, Lia R.

AU - Fondevilla, Constantino

AU - Stärkel, Peter

AU - Dubuquoy, Laurent

AU - Louvet, Alexandre

AU - Odena, Gemma

AU - Gomez, Juan L.

AU - Aragon, Tomas

AU - Altamirano, Jose

AU - Caballeria, Juan

AU - Jurczak, Michael J.

AU - Taylor, D. Lansing

AU - Berasain, Carmen

AU - Wahlestedt, Claes R

AU - Monga, Satdarshan P.

AU - Morgan, Marsha Y.

AU - Sancho-Bru, Pau

AU - Mathurin, Philippe

AU - Furuya, Shinji

AU - Lackner, Carolin

AU - Rusyn, Ivan

AU - Shah, Vijay H.

AU - Thursz, Mark R.

AU - Mann, Jelena

AU - Avila, Matias A.

AU - Bataller, Ramon

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