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

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.

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