Trends in Genetics
ReviewUnraveling the Epigenetic Basis of Liver Development, Regeneration and Disease
Section snippets
Epigenetics and Epigenesis
The history of epigenetics is intertwined with the theory of ‘epigenesis’, an idea that tissues form anew from undifferentiated cells during development or regeneration. Originally proposed in the 1700s, this theory integrated philosophy and experimental science to propose that a series of differentiation and morphogenesis steps are required for organisms to form new structures. The idea that cells with one identity can turn into something else entirely has laid the foundation for modern
The Chromatin Landscape Orchestrates Liver Development
The vast array of functions carried out by the liver are largely performed by hepatocytes, the most abundant cell type in the liver. Hepatocytes are integrated with biliary epithelial cells (BECs) and cells from endothelial, immune, and fibroblast lineages into a distinct cellular architecture that is species specific [3]. The functional and molecular similarities between the cells in zebrafish, mouse, and human liver make the first two animal models excellent systems to study hepatic
Epigenetics and Liver Regeneration
In most scenarios, regeneration of injured or amputated tissues relies on epigenesis, whereby stem cells and repurposed differentiated cells are reprogrammed to form new structures (Box 2). However, the mammalian liver has the unique capacity to regenerate through hepatocyte proliferation, a capacity that likely evolved due to the important role that the liver plays in the frontline defense against toxins and other stimuli that cause cell injury (Figure 1). The hope that conferring the
Concluding Remarks
Chronic liver injury caused by toxins, metabolic diseases, viral infection, alcohol abuse, or metabolic syndrome triggers signals to replace damaged hepatocytes by continual hepatocyte proliferation. When regeneration is not sufficient to repair the damage, liver disease results. Epigenetic mechanisms orchestrate many aspects of liver fibrogenesis [68], and epigenetic factors are influenced by environmental factors in fatty liver [69]. The best understood relationship between epigenetics and
Acknowledgments
The authors are grateful to J. Chu and members of the Sadler laboratory for helpful comments on this review. This work was supported in part by the Al Jalila Foundation, the NYUAD Research Enhancement Fund, and the Abu Dhabi Education and Knowledge Council.
Glossary
- Assay for transposase-accessible chromatin using sequencing (ATAC-seq)
- a technique to determine the chromatin accessibility across the whole genome.
- Bromodomain and extra-terminal motif (BET) proteins
- 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 followed by sequencing (ChIP-seq)
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Cited by (21)
Loss of liver function in chronic liver disease: An identity crisis
2023, Journal of HepatologyCitation Excerpt :After birth, an increasingly complex set of cross-regulated TFs, plus signalling systems such as WNT and Notch, and splicing regulators, define the liver zonal architecture and consolidate mature hepatocellular function.2,6–8 An intricate system of signals, TFs and epigenetic mechanisms secure the preservation of the liver-specific gene expression pattern (i.e. hepatocellular identity) in adulthood.9,10 The robust nature of this network is essential to maintain liver function and systemic homeostasis.11
DNA methylation in cell plasticity and malignant transformation in liver diseases
2023, Pharmacology and TherapeuticsCitation Excerpt :First, chromatin remodelers modify the nucleosome to close and/or expose gene loci of transcription regulation complexes. Next, a variety of repressors, enhancers, and activators are recruited to perform the necessary duty to execute lineage commitment (Aloia, 2021; Basu & Tiwari, 2021; Greenberg & Bourc'his, 2019; Macchi & Sadler, 2020; Martinez-Redondo & Izpisua Belmonte, 2020). In general, epigenetic regulation for chromatin remodeling consists of 1) post-translational histone modifications such as acetylation, methylation, phosphorylation, amination, etc.; 2) exchange of core histones with histone variants; 3) action of various non-coding RNAs; and 4) DNA methylation of CpG islands.
A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver
2022, GenomicsCitation Excerpt :Nearly all previously published work on Atf6 focuses on its role in responding to ER stress due to toxicant exposure, however there are many other scenarios where ER stress occurs as part of a normal physiological process. For instance, liver regeneration following PH of 2/3 of liver mass depends on synchronous proliferation of hepatocytes to restore liver mass within 96–120 h [68]. During this time, hepatic function is maintained by increasing the secretory output of the regenerating hepatocytes.
Epithelial Plasticity during Liver Injury and Regeneration
2020, Cell Stem CellCitation Excerpt :In the quiescent liver, the epigenome ensures a stable state of differentiation within hepatocytes. Epigenetic remodeling, through DNA methylation, histone modification, and chromatin remodeling, is ultimately responsible for deciding which genes are turned on or off in a particular cell, generating a transcriptomic switch that allows cells to re-enter the cell cycle (Macchi and Sadler, 2020). Identifying critical epigenetic modifications can be complicated by intricate compensatory mechanisms.