Epigenetic Regulation of Cell-Fate Changes That Determine Adult Liver Regeneration After Injury

Abstract

The adult liver has excellent regenerative potential following injury. In contrast to other organs of the body that have high cellular turnover during homeostasis (e.g., intestine, stomach, and skin), the adult liver is a slowly self-renewing organ and does not contain a defined stem-cell compartment that maintains homeostasis. However, tissue damage induces significant proliferation across the liver and can trigger cell-fate changes, such as trans-differentiation and de-differentiation into liver progenitors, which contribute to efficient tissue regeneration and restoration of liver functions. Epigenetic mechanisms have been shown to regulate cell-fate decisions in both embryonic and adult tissues in response to environmental cues. Underlying their relevance in liver biology, expression levels and epigenetic activity of chromatin modifiers are often altered in chronic liver disease and liver cancer. In this review, I examine the role of several chromatin modifiers in the regulation of cell-fate changes that determine efficient adult liver epithelial regeneration in response to tissue injury in mouse models. Specifically, I focus on epigenetic mechanisms such as chromatin remodelling, DNA methylation and hydroxymethylation, and histone methylation and deacetylation. Finally, I address how altered epigenetic mechanisms and the interplay between epigenetics and metabolism may contribute to the initiation and progression of liver disease and cancer.

The influence of tissue spatial geometry and functional organisation on liver regeneration

“…Toxic injury induces biliary proliferation and expansion of biliary ducts in both mouse and human liver, a phenomenon called ductular reaction [45]. These expanding ductal branches are associated with the establishment of bipotent liver progenitors capable of regenerating the epithelial compartment after damage [6,8,46]. Both adult liver epithelial cell types can de-differentiate into bipotent liver progenitors, consistent with the developmental origin of both hepatocytes and intrahepatic cholangiocytes from a common embryonic progenitor, the hepatoblast [2,3,24].…”

“…Therefore, this confirms that the majority of the hepatocytes can acquire proliferation and that the spatial location within the liver lobule determines the activation of specific hepatocyte subpopulations according to the type of injury. The next challenge will be to determine the role of regional metabolic inputs and hepatocyte competence in the regulation of the epigenetic and transcriptional mechanisms that promote liver regeneration after damage [8].…”

“…This is even more remarkable considering that the adult liver is a slowly self-renewing organ and lacks an evident stem-cell compartment in homeostasis, opposite to other highly regenerative organs such as intestine, stomach and skin. Thus, cellular plasticity awakens liver cells in response to damage and induces cell-fate changes, such as cell trans-differentiation and de-differentiation into progenitors, to achieve efficient liver regeneration [5][6][7][8]. However, persistent liver injury, caused by alcohol abuse, metabolic dysfunctions, severe obesity and viral infections, overwhelms liver regenerative capacity and impairs liver function, causing chronic liver disease and predisposing to liver cancer [9].…”

Obesity, the Obesity Epidemic, and Metabolic Dysfunction: The Conundrum Presented by the Disconnect between Evolution and Modern Societies

“…Thus, having genetic/epigenetic tools to enhance food storage and retain the energy content of foods to successfully get through shortages may be a very different scenario from development of chronic obesity which may convert the multitude of genetic risk factors into the chronic form with associated acute-to-chronic modifications which make turning back either difficult or not possible! In other chronic diseases, the development of a chronic disease or state is often accompanied by epigenetic alterations that can change the landscape dramatically [17][18][19].…”

A Comprehensive In Silico Perspective For Discovery of Novel Inhibitory Candidates Targeting Versatile Transcriptional Repressor MBD2

“…Epigenetic regulation is a key process in which involves various mechanisms, dynamically altering and specifying gene expression and cell fate (Aloia, 2021). As a predominant epigenetic mechanism, DNA methylation involves covalent attachment of methyl groups (-CH 3 ) from S-adenosyl-L-methionine as the methyl donor to the carbon-5 positions (C5) of the cytosine residues within a context of cytosine-guanine (CpG) dinucleotides resulting in 5-methylcytosine (5-mC) analogue (Moore et al, 2013).…”