Unraveling the Epigenetic Basis of Liver Development, Regeneration and Disease

An epigenetic prepattern governs fate decisions and differentiation potential during liver development. Liver regeneration is accompanied by a coordinated set of gene expression changes, which could be regulated by an epigenetic pattern in quiescent hepatocytes, thereby governing regenerative potential. Recent studies suggest that broad changes to the epigenetic landscape during liver regeneration control the expression of genes driving regeneration and the ones dictating hepatic fate. A wealth of studies over several decades has revealed an epigenetic prepattern that determines the competence of cellular differentiation in the developing liver. More recently, studies focused on the impact of epigenetic factors during liver regeneration suggest that an epigenetic code in the quiescent liver may establish its regenerative potential. We review work on the pioneer factors and other chromatin remodelers that impact the gene expression patterns instructing hepatocyte and biliary cell specification and differentiation, along with the requirement of epigenetic regulatory factors for hepatic outgrowth. We then explore recent studies involving the role of epigenetic regulators, Arid1a and Uhrf1, in efficient activation of proregenerative genes during liver regeneration, thus highlighting the epigenetic mechanisms of liver disease and tumor development. A wealth of studies over several decades has revealed an epigenetic prepattern that determines the competence of cellular differentiation in the developing liver. More recently, studies focused on the impact of epigenetic factors during liver regeneration suggest that an epigenetic code in the quiescent liver may establish its regenerative potential. We review work on the pioneer factors and other chromatin remodelers that impact the gene expression patterns instructing hepatocyte and biliary cell specification and differentiation, along with the requirement of epigenetic regulatory factors for hepatic outgrowth. We then explore recent studies involving the role of epigenetic regulators, Arid1a and Uhrf1, in efficient activation of proregenerative genes during liver regeneration, thus highlighting the epigenetic mechanisms of liver disease and tumor development. a technique to determine the chromatin accessibility across the whole genome. contain a structural motif (the bromodomain) that recognizes acetylated lysine residues on histones. BET inhibitors block interaction between BET proteins and are used as cancer therapy due to the frequent deregulation of BETs in cancer. chromatin immunoprecipitation is a technique to determine DNA–protein interaction. It can be performed to detect the binding sites of transcription/repressive factors or to determine the pattern of hPTMs and histone variants. these are protein complexes that use ATP to restructure nucleosome position. These include the SWI/SNF complex, which contains Arid1a and the BETs. DNA methylation is the most studied DNA modification, and it occurs at the 5-methylcitosine in the CG dinucleotide (CpG). DNA methylation causes a condensation of the DNA fibers; thus, it is involved in imprinting and repression of repetitive elements, such as retrotransposons. Even if numerous studies show a correlation between hypermethylation of gene promoters and gene silencing, there is no evidence that DNA methylation controls gene expression in terminal differentiated tissues. In fact, most gene promoters are devoid of DNA methylation. During the cell cycle, DNA methylation is maintained by DNA methyltransferase 1 (Dnmt1) that is recruited by ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) on the hemimethylated site at the replication forks. De novo DNA methylation is carried out by DNMT3A and DNMT3B in mammals. the modifications that control genome regulation and accessibility without affecting its sequence. The epigenome is central to regulating gene transcription, TE suppression, cell fate, and differentiation. acetylation of histone tails by histone acetyltransferases (HATs, such as p300) in H3K27ac, H3K9ac, or H3K14ac open the chromatin. Histone deacetylases (HDACs) reverse this and lead to closed chromatin. HDAC inhibitors are used to keep the chromatin open but these also target many other acetyltransferases. histone tails can undergo more than 60 different PTMs, such as methylation, acetylation, ubiquitylation, sumoylation, phosphorylation, ADP ribosylation, and proline isomerization. This combination is referred to as the ‘histone code.’ Each of these modifications regulate the accessibility of the chromatin by compacting or dispersing the nucleosomes. Although, typically, histone methylations condense the nucleosomes (i.e., methylation of lysine 9 of histone 3 -H3K9me1me2me3- or trimethylation of lysine 27 of histone 3 -H3K27me3-). Exceptions include: H3K4me3, associated to active promoter region of transcribed genes, and H3K4me1, localized to active enhancers. histone variants are noncanonical variants of histones, containing one or a few different amino acids that are usually expressed at low levels compared to the canonical version. They have specific expression patterns in different tissues and time of development, and they specifically localize in distinct regions of the genome, affecting hPTMs and chromatin regulation. the fundamental structural unit of the chromatin. Each nucleosome is composed of 146 bp of DNA wrapped around eight core proteins called histones. Each octamer is composed of two copies of H2A, H2B, H3, and H4. The nucleosomes are connected by linker DNA and one linker histone, H1 or H5. a class of TFs that possess the unique ability to initiate chromatin opening by engaging their target sites with displacement of the linker histones. They also recruit chromatin remodeling complexes and tissue-specific regulatory TFs and are important for several developmental processes. these ‘jumping genes’, also called transposons, discovered by McClintock, are remnants of ancient viruses that have become incorporated into the genomes of most organisms. TEs are repetitive sequences found in multiple copies due to their mobility. While most TEs have degenerated during evolution so they no longer pose a threat, the potential damage that mobile DNA can have on genome structure has resulted in the evolution mechanisms of suppressing TE activation. In vertebrates, most TEs are suppressed by DNA methylation as well as other repressive epigenetic marks.