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Open Access Highly Accessed Research article

ChIP-seq in steatohepatitis and normal liver tissue identifies candidate disease mechanisms related to progression to cancer

Madhusudhan Bysani1, Ola Wallerman15, Susanne Bornelöv2, Kurt Zatloukal3, Jan Komorowski24 and Claes Wadelius1*

Author Affiliations

1 Science for Life Laboratory, Department of Immunology, Genetics and Pathology, BMC, Uppsala University, PO BOX 815, Uppsala, SE 751 08, Sweden

2 Science for Life Laboratory, Department of Cell and Molecular Biology, BMC, Uppsala University, Uppsala, Sweden

3 Institute of Pathology, Medical University of Graz, Graz, Austria

4 Interdisciplinary Centre for Mathematical and Computational Modelling, University of Warsaw, Warsaw, PL-02-106, Poland

5 Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, BMC, Uppsala, Sweden

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BMC Medical Genomics 2013, 6:50  doi:10.1186/1755-8794-6-50

Published: 8 November 2013

Abstract

Background

Steatohepatitis occurs in alcoholic liver disease and may progress to liver cirrhosis and hepatocellular carcinoma. Its molecular pathogenesis is to a large degree unknown. Histone modifications play a key role in transcriptional regulations as marks for silencing and activation of gene expression and as marks for functional elements. Many transcription factors (TFs) are crucial for the control of the genes involved in metabolism, and abnormality in their function may lead to disease.

Methods

We performed ChIP-seq of the histone modifications H3K4me1, H3K4me3 and H3K27ac and a candidate transcription factor (USF1) in liver tissue from patients with steatohepatitis and normal livers and correlated results to mRNA-expression and genotypes.

Results

We found several regions that are differentially enriched for histone modifications between disease and normal tissue, and qRT-PCR results indicated that the expression of the tested genes strongly correlated with differential enrichment of histone modifications but is independent of USF1 enrichment. By gene ontology analysis of differentially modified genes we found many disease associated genes, some of which had previously been implicated in the etiology of steatohepatitis. Importantly, the genes associated to the strongest histone peaks in the patient were over-represented in cancer specific pathways suggesting that the tissue was on a path to develop to cancer, a common complication to the disease. We also found several novel SNPs and GWAS catalogue SNPs that are candidates to be functional and therefore needs further study.

Conclusion

In summary we find that analysis of chromatin features in tissue samples provides insight into disease mechanisms.

Keywords:
ChIP-seq; Tissue samples; Steatohepatitis; Cancer networks