Research Papers: Pathology:

Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells

Adil El Taghdouini _, Anita L. Sørensen, Andrew H. Reiner, Mar Coll, Stefaan Verhulst, Inge Mannaerts, Cristina I. Øie, Bård Smedsrød, Mustapha Najimi, Etienne Sokal, Aernout Luttun, Pau Sancho-Bru, Philippe Collas and Leo A. van Grunsven

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Oncotarget. 2015; 6:26729-26745. https://doi.org/10.18632/oncotarget.4925

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Adil El Taghdouini1,*, Anita L. Sørensen2,*, Andrew H. Reiner2, Mar Coll3, Stefaan Verhulst1, Inge Mannaerts1, Cristina I. Øie4, Bård Smedsrød4, Mustapha Najimi5, Etienne Sokal5, Aernout Luttun6, Pau Sancho-Bru3, Philippe Collas2, Leo A. van Grunsven1

1Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Brussels, Belgium

2Department of Molecular medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway

3Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

4Department of Medical Biology, Vascular Biology Research Group, UiT, The Arctic University of Norway, Tromsø, Norway

5Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique (IREC), Laboratory of Pediatric Hepatology and Cell Therapy, Brussels, Belgium

6Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven (KU Leuven), Leuven, Belgium

*These authors have contributed equally to this work

Correspondence to:

Leo A. van Grunsven, e-mail: [email protected]

Philippe Collas, e-mail: [email protected]

Keywords: Pathology section, hepatic stellate cells, liver fibrosis, DNA methylation, epigenetics

Received: July 08, 2015     Accepted: August 20, 2015     Published: August 31, 2015


Background & Aims: Liver fibrogenesis – scarring of the liver that can lead to cirrhosis and liver cancer – is characterized by hepatocyte impairment, capillarization of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cell (HSC) activation. To date, the molecular determinants of a healthy human liver cell phenotype remain largely uncharacterized. Here, we assess the transcriptome and the genome-wide promoter methylome specific for purified, non-cultured human hepatocytes, LSECs and HSCs, and investigate the nature of epigenetic changes accompanying transcriptional changes associated with activation of HSCs.

Material and methods: Gene expression profile and promoter methylome of purified, uncultured human liver cells and culture-activated HSCs were respectively determined using Affymetrix HG-U219 genechips and by methylated DNA immunoprecipitation coupled to promoter array hybridization. Histone modification patterns were assessed at the single-gene level by chromatin immunoprecipitation and quantitative PCR.

Results: We unveil a DNA-methylation-based epigenetic relationship between hepatocytes, LSECs and HSCs despite their distinct ontogeny. We show that liver cell type-specific DNA methylation targets early developmental and differentiation-associated functions. Integrative analysis of promoter methylome and transcriptome reveals partial concordance between DNA methylation and transcriptional changes associated with human HSC activation. Further, we identify concordant histone methylation and acetylation changes in the promoter and putative novel enhancer elements of genes involved in liver fibrosis.

Conclusions: Our study provides the first epigenetic blueprint of three distinct freshly isolated, human hepatic cell types and of epigenetic changes elicited upon HSC activation.

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