Epigenetic mechanisms, such as histone (de)acetylation and DNA methylation, as well as diverse posttranslational histone modifications, modulate the chromatin compaction status and hence affect the transcriptional activity of genes.
Earlier we could show that gene expression changes occurring during hepatocyte dedifferentiation and leading to functionality loss can be modulated by exposure to epigenetic modifiers, such as histone deacetylase inhibitors (HDACi), resulting in:
- maintenance of hepatic functions, incuding the expression and activity of specific Cytochrome P450 (CYPs) enzymes, secretion of albumin and functional gap junctional intercellular communication (GJIC),
- higher survival rate of hepatocytes in conventional monolayer culture due to delayed activation of programmed cell death pathways.
Moreover, simultaneous exposure to a DNA methyltransferase inhibitor (DNMTi) potentiated the effect of HDAC inhibition, pointing towards synergetic behaviour of HDACi and DNMTi in the acquisition and maintenance of a differentiated hepatic phenotype.
We explored the role of epigenetic mechanisms, such as histone deacetylation and DNA methylation, in the regulation of the expression and function of hepatic drug transporters in cultures of primary hepatocytes.
Relevant Publications
- Elaut G., Henkens T., Papeleu P., Snykers S., Vinken M., Vanhaecke T. and Rogiers V. (2006) Molecular mechanisms underlying the dedifferentiation process of isolated hepatocytes and their cultures. Current Drug Metabolism 7(6), 629-660.
- Papeleu P., Wullaert A., Elaut G., Henkens T., Vinken M., Laus G., Tourwé D., Beyaert R., Rogiers V. and Vanhaecke T. (2006) Inhibition of NF-κB activation by the histone deacetylase inhibitor 4-Me2N-BAVAH induces an early G1 cell cycle arrest in primary hepatocytes. Cell Proliferation 40, 640-655.
- Vinken M., Henkens T., Vanhaecke T., Papeleu P., Geerts A., Van Rossen E., Chipman J.K., Meda P., Rogiers V. (2006) Trichostatin A enhances gap junctional intercellular communication in primary cultures of adult rat hepatocytes. Toxicological Sciences 91: 484-492.
- Henkens T., Papeleu P., Elaut G., Vinken M., Rogiers V. and Vanhaecke T. (2007) Trichostatin A, a critical factor in maintaining the functional differentiation of primary cultured rat hepatocytes. Toxicology and Applied Pharmacology 218(1), 64-71.
- Fraczek J., Vinken M., Tourwé D., Vanhaecke T. and Rogiers V. (2012) Synergetic effects of DNA demethylation and histone deacetylase inhibition in primary rat hepatocytes. Investigational New Drugs. 30: 1715--1724.
- Ramboer E, Vanhaecke T, Rogiers V, Vinken M (2013) Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. Drug Metabolism Reviews 45: 196-217.