Unraveling the Epigenetic Basis of Liver Development, Regeneration and Disease

doi:10.1016/j.tig.2020.05.002

Trends in Genetics

Volume 36, Issue 8, August 2020, Pages 587-597

https://doi.org/10.1016/j.tig.2020.05.002 Get rights and content

Highlights

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.

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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Citation 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
Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.
DNA methylation in cell plasticity and malignant transformation in liver diseases
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Citation 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.
The liver possesses extraordinary regenerative capacity mainly attributable to the ability of hepatocytes (HCs) and biliary epithelial cells (BECs) to self-replicate. This ability is left over from their bipotent parent cell, the hepatoblast, during development. When this innate regeneration is compromised due to the absence of proliferative parenchymal cells, such as during cirrhosis, HCs and BEC can transdifferentiate; thus, adding another layer of complexity to the process of liver repair. In addition, dysregulated lineage maintenance in these two cell populations has been shown to promote malignant growth in experimental conditions. Here, malignant transformation, driven in part by insufficient maintenance of lineage reprogramming, contributes to end-stage liver disease. Epigenetic changes are key drivers for cell fate decisions as well as transformation by finetuning overall transcription and gene expression. In this review, we address how altered DNA methylation contributes to the initiation and progression of hepatic cell fate conversion and cancer formation. We also discussed the diagnostic and therapeutic potential of targeting DNA methylation in liver cancer, its current limitations, and what future research is necessary to facilitate its contribution to clinical translation.
A permissive epigenetic landscape facilitates distinct transcriptional signatures of activating transcription factor 6 in the liver
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Citation 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.
Restoring homeostasis following proteostatic stress hinges on a stress-specific transcriptional signature. How these signatures are regulated is unknown. We use functional genomics to uncover how activating transcription factor 6 (ATF6), a central factor in the unfolded protein response, regulates its target genes in response to toxicant induced and physiological stress in the liver. We identified 652 conserved putative ATF6 targets (CPATs), which functioned in metabolism, development and proteostasis. Strikingly, Atf6 activation in the zebrafish liver by transgenic nAtf6 overexpression, ethanol and arsenic exposure resulted in a distinct CPAT signature for each; with only 34 CPATs differentially expressed in all conditions. In contrast, during liver regeneration in mice resulted in a dynamic differential expression pattern of 53% of CPATs. These CPATs were distinguished by residing in open chromatin, H3K4me3 occupancy and the absence of H3K27me3 on their promoters. This suggests that a permissive epigenetic landscape allows stress-specific Atf6 target gene expression.
Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg
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Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.
Epithelial Plasticity during Liver Injury and Regeneration
2020, Cell Stem Cell
Citation 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.
Following injury, the liver’s epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
Lung regeneration: diverse cell types and the therapeutic potential
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Trends in Genetics

ReviewUnraveling the Epigenetic Basis of Liver Development, Regeneration and Disease

Highlights

Section snippets

Epigenetics and Epigenesis

The Chromatin Landscape Orchestrates Liver Development

Epigenetics and Liver Regeneration

Concluding Remarks

Acknowledgments

Glossary

J. Hepatol.

Semin. Cell Dev. Biol.

Gastroenterology

Curr. Top. Dev. Biol.

Gastroenterology

Methods Cell Biol.

Cell Stem Cell

Dev. Biol.

Mol. Cell

Stem Cell Reports

Mol. Cell

Gastroenterology

Dev. Biol.

Differentiation

Cell

Dev. Biol.

Dev. Biol.

Curr. Biol.

J. Hepatol.

J. Biol. Chem.

Hepatology

Cell Stem Cell

Cell

Cell. Mol. Gastroenterol. Hepatol.

Cell Stem Cell

FEBS Lett.

Transplant. Proc.

Cancer Cell

Am. J. Pathol.

Cell. Mol. Gastroenterol. Hepatol.

J. Hepatol.

Cancer Cell

Cell

Dev. Biol.

Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury

Hepatology

Notch inhibition promotes differentiation of liver progenitor cells into hepatocytes via sox9b repression in zebrafish

Stem Cells Int.

De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation

Nature

Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes

Cell Stem Cell

Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish

Gastroenterology

Orchestrating liver development

Development

New school in liver development: lessons from zebrafish

Hepatology

Review
Unraveling the Epigenetic Basis of Liver Development, Regeneration and Disease