Role of epigenetics in liver-specific gene transcription, hepatocyte differentiation and stem cell reprogrammation☆

published online 02 April 2009.

Controlling both growth and differentiation of stem cells and their differentiated somatic progeny is a challenge in numerous fields, from preclinical drug development to clinical therapy. Recently, new insights into the underlying molecular mechanisms have unveiled key regulatory roles of epigenetic marks driving cellular pluripotency, differentiation and self-renewal/proliferation. Indeed, the transcription of genes, governing cell-fate decisions during development and maintenance of a cell’s differentiated status in adult life, critically depends on the chromatin accessibility of transcription factors to genomic regulatory and coding regions. In this review, we discuss the epigenetic control of (liver-specific) gene-transcription and the intricate interplay between chromatin modulation, including histone (de)acetylation and DNA (de)methylation, and liver-enriched transcription factors. Special attention is paid to their role in directing hepatic differentiation of primary hepatocytes and stem cells in vitro.

Associate Editor: C. Trautwein

Abbreviations: ADSC, adipose tissue-derived stem cells, ALB, albumin, AFP, alpha-fetoprotein, AhR, aryl hydrocarbon receptor, 5-AzaC, 5-Azacytidine or azacytidine, 5-Aza-dC, 5-Aza-2′-deoxycytidine or decitabine, C/EBP, CCAAT/Enhancer Binding Protein, CYP, cytochrome P450, CBP, CREB-binding protein, CpGs, cytosine-guanine dinucleotides, DHAC, 5-6-Dihydro-5-azacytidine, 4-Me2N-BAVAH, 5-(4-dimethylaminobenzoyl)-aminovaleric acid hydroxamide, DNMTs, DNA methyltransferases, DNMTi, DNMT inhibitors, ES, embryonic stem cells, EGF, epidermal growth factor, EGCG, (-)-epigallocatechin-3-gallate, HCC, hepatocellular carcinoma, HNF, hepatocyte nuclear factor, HATs, histone acetyl transferases, HDACs, histone deacetylases, HDACi, hydroxamate-based HDAC inhibitors, iPS, induced pluripotent cells, LETFs, liver-specific transcription factors, MSC, mesenchymal stem/progenitor cells, MBD, methylated DNA-binding protein, P/CAF, p300/CBP-associated factor, PGC-1α, PPAR-gamma coactivator 1alpha, zebularine, 2-Pyrimidone-1-β-D-riboside, TSA, Trichostatin A, VPA, valproic acid

Keywords: Epigenetics, DNA methyltransferase inhibitor, Histone deacetylase inhibitor, Liver-enriched transcription factors, Stem cells, Primary hepatocytes, Differentiation

1 Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium

2 Department of Cell Biology, Vrije Universiteit Brussels, Brussels, Belgium

Corresponding author. Tel.: +32 02 4774518; fax: +32 02 4774582.

☆ The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.

# These authors contributed equally to this work.

‡ These authors are post doctoral research fellows of the Fund for Scientific Research Flanders (FWO-Vlaanderen) Belgium.

† Deceased.

PII: S0168-8278(09)00171-8

doi:10.1016/j.jhep.2009.03.009

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