Epigenetics during hepatic stellate cell activation

In normal liver, hepatic stellate cells (HSC) are quiescent and store retinoids, but they become activated after liver injury and can contribute to tissue repair or fibrosis. During this activation process, HSC develop into... [ view full abstract ]

In normal liver, hepatic stellate cells (HSC) are quiescent and store retinoids, but they become activated after liver injury and can contribute to tissue repair or fibrosis. During this activation process, HSC develop into myofibroblast-like cells and substantially alter their gene expression. The involvement of epigenetic mechanisms in the activation process of isolated rat HSC was investigated in the present study by combined methylome and transcriptome analysis using genome-wide sequencing and gene expression arrays. The activation process of HSC was accompanied by strong DNA demethylation of about 60% within the first 3 days of culture, which was apparently not restricted to methylated cytosine in CpG rich regions, since the majority of analyzed genes showed hyper- but not hypomethylation during activation and repetitive DNA sequences remained unaffected. However, the DNA demethylation could not be explained by elevated DNA synthesis, but seem to involve an active demethylation mechanism, which awaits further characterization. Gene ontology (GO) term analysis of differentially methylated and expressed genes revealed that the majority of genes were enriched in the GO terms “response to stress” and “cell differentiation”. While the first GO term could be explained by the cell isolation and culture procedure, the latter GO term indicated a developmental potential of HSC, which supports their classification as mesenchymal stem cells. In conclusion, the HSC activation in vitro was found to be associated with profound changes in their methylome and transcriptome and, thus, epigenetic mechanisms seem to be important for the control of HSC activation and development.