Abstract:
:Non-alcoholic steatohepatitis (NASH) is becoming one of the major causes of hepatocellular carcinoma (HCC) in the United States and Western countries; however, the molecular mechanisms associated with NASH-related liver carcinogenesis are not well understood. In the present study, we investigated cancer-associated chromatin alterations using a model that resembles the development of NASH-related HCC in humans. An assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) identified 1677 tumor-specific chromatin-accessible regions in NASH-derived HCC tissue samples. Using a combined analysis of ATAC-seq and global gene expression data, we identified 199 differentially expressed genes, 139 up-regulated and 60 down-regulated. Interestingly, 15 of the 139 up-regulated genes had accessible chromatin sites within 5 Kb of the transcription start site (TSS), including Apoa4, Anxa2, Serpine1, Igfbp1, and Tubb2a, genes critically involved in the development of NASH and HCC. We demonstrate that the mechanism for the up-regulation of these genes is associated with the enrichment of chromatin-accessible regions by transcription factors, especially NFATC2, and histone H3K4me1 and H3K27ac gene transcription-activating marks. These data underline the important role of chromatin accessibility perturbations in reshaping of the chromatin landscape in NASH-related HCC.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Dechassa ML,Tryndyak V,de Conti A,Xiao W,Beland FA,Pogribny IPdoi
10.1002/mc.22818subject
Has Abstractpub_date
2018-08-01 00:00:00pages
978-987issue
8eissn
0899-1987issn
1098-2744journal_volume
57pub_type
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