The epigenetic landscape and evolution.

Waddington's epigenetic landscape illustrates such characteristic features of development as homeorhesis and the existence of alternative developmental pathways. Simply recongnizing that these are typical allows us to make inferences about evolution, for example that macroevolution is often a different process from microevolution. We can account for the origin of these properties by assuming that many processes in development can be modelled by non-linear differential equatiions. The assumption then leads to two further predictions: that multiple speciation may be relatively common and that phenocopying is likely to occur in one direction only.     

JMJD3 as an epigenetic regulator in development and disease

Gene expression is epigenetically regulated through DNA methylation and covalent chromatin modifications, such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation of histones. Histone methylation state is dynamically regulated by different groups of histone methyltransferases and demethylases. The trimethylation of histone 3 (H3K4) at lysine 4 is usually associated with the activation of gene expression, whereas trimethylation of histone 3 at lysine 27 (H3K27) is associated with the repression of gene expression. The polycomb repressive complex contains the H3K27 methyltransferase Ezh2 and controls dimethylation and trimethylation of H3K27 (H3K27me2/3). The Jumonji domain containing-3 (Jmjd3, KDM6B) and ubiquitously transcribed X-chromosome tetratricopeptide repeat protein (UTX, KDM6A) have been identified as H3K27 demethylases that catalyze the demethylation of H3K27me2/3. The role and mechanisms of both JMJD3 and UTX have been extensively studied for their involvement in development, cell plasticity, immune system, neurodegenerative disease, and cancer. In this review, we will focus on recent progresses made on understanding JMJD3 in the regulation of gene expression in development and diseases. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.     

IGF2: epigenetic regulation and role in development and disease

Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted – only one allele is active, depending on parental origin – and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.     

Navigating the epigenetic landscape of pluripotent stem cells

Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, use a complex network of genetic and epigenetic pathways to maintain a delicate balance between self-renewal and multilineage differentiation. Recently developed high-throughput genomic tools greatly facilitate the study of epigenetic regulation in pluripotent stem cells. Increasing evidence suggests the existence of extensive crosstalk among epigenetic pathways that modify DNA, histones and nucleosomes. Novel methods of mapping higher-order chromatin structure and chromatin-nuclear matrix interactions also provide the first insight into the three-dimensional organization of the genome and a framework in which existing genomic data of epigenetic regulation can be integrated to discover new rules of gene regulation.     

Bistability, bifurcations, and Waddington's epigenetic landscape

Waddington's epigenetic landscape is probably the most famous and most powerful metaphor in developmental biology. Cells, represented by balls, roll downhill through a landscape of bifurcating valleys. Each new valley represents a possible cell fate and the ridges between the valleys maintain the cell fate once it has been chosen. Here I examine models of two important developmental processes - cell-fate induction and lateral inhibition - and ask whether the landscapes for these models at least qualitatively resemble Waddington's picture. For cell-fate induction, the answer is no. The commitment of a cell to a new fate corresponds to the disappearance of a valley from the landscape, not the splitting of one valley into two, and it occurs through a type of bifurcation - a saddle-node bifurcation - that possesses an intrinsic irreversibility that is missing from Waddington's picture. Lateral inhibition, a symmetrical cell-cell competition process, corresponds better to Waddington's picture, with one valley reversibly splitting into two through a pitchfork bifurcation. I propose an alternative epigenetic landscape that has numerous valleys and ridges right from the start, with the process of cell-fate commitment corresponding to the irreversible disappearance of some of these valleys and ridges, via cell-fate induction, complemented by the creation of new valleys and ridges through processes like cell-cell competition.     

A glimpse into the epigenetic landscape of gene regulation

Post-translational modifications to histone proteins and methylation of DNA comprise the epigenome of a cell. The epigenome, which changes through development, controls access to our genes. Recent advances in DNA sequencing technology has led to genome-wide distribution data for a limited number of histone modifications in mammalian stem cells and some differentiated lineages. These studies reveal predictive correlations between histone modifications, different classes of gene and chromosomal features. Moreover, this glimpse into our epigenome challenges current ideas about regulation of gene expression. Many genes in stem cells are poised for expression with initiated RNA polymerase II at the promoter. This state is maintained by an epigenetic mark through multiple lineages until the gene is expressed.     

On the role of retinoblastoma family proteins in the establishment and maintenance of the epigenetic landscape

RB family members are negative regulators of the cell cycle, involved in numerous biological processes such as cellular senescence, development and differentiation. Disruption of RB family pathways are linked to loss of cell cycle control, cellular immortalization and cancer. RB family, and in particular the most studied member RB/p105, has been considered a tumor suppressor gene by more than three decades, and numerous efforts have been done to understand his molecular activity. However, the epigenetic mechanisms behind Rb‐mediated tumor suppression have been uncovered only in recent years. In this review, the role of RB family members in cancer epigenetics will be discussed. We start with an introduction to epigenomes, chromatin modifications and cancer epigenetics. In order to provide a clear picture of the involvement of RB family in the epigenetic field, we describe the RB family role in the epigenetic landscape dynamics based on the heterochromatin variety involved, facultative or constitutive. We want to stress that, despite dissimilar modulations, RB family is involved in both mammalian varieties of heterochromatin establishment and maintenance and that disruption of RB family pathways drives to alterations of both heterochromatin structures, thus to the global epigenetic landscape. J. Cell. Physiol. 228: 276–284, 2013. © 2012 Wiley Periodicals, Inc.     

Transgenerational epigenetic inheritance in health and disease

Over the past century, patterns of phenotypic inheritance have been observed that are not easily rationalised by Mendel's rules of inheritance. Now that we have begun to understand more about non-DNA based, or 'epigenetic', control of phenotype at the molecular level, the idea that the transgenerational inheritance of these epigenetic states could explain non-Mendelian patterns of inheritance has become attractive. There is a growing body of evidence that abnormal epigenetic states, termed epimutations, are associated with disease in humans. For example, in several cases of colorectal cancer, epimutations have been identified that silence the human mismatch repair genes, MLH1 and MSH2. But strong evidence that the abnormal epigenetic states are primary events that occur in the absence of genetic change and are inherited across generations is still absent.     

Transcriptional and epigenetic landscape of Ca2+-signaling genes in hepatocellular carcinoma

Calcium (Ca²⁺) signaling has a major role in regulating a wide range of cellular mechanisms, including gene expression, proliferation, metabolism, cell death, muscle contraction, among others. Recent evidence suggests that ~ 1600 genes are related to the Ca²⁺ signaling. Some of these genes’ expression is altered in several pathological conditions, including different cancer types, and epigenetic mechanisms are involved. However, their expression and regulation in hepatocellular carcinoma (HCC) and the liver are barely known. Here, we aimed to explore the expression of genes involved in the Ca²⁺-signaling in HCC, liver regeneration, and hepatocyte differentiation, and whether their expression is regulated by epigenetic mechanisms such as DNA methylation and histone posttranslational modifications (HPM). Results show that several Ca²⁺-signaling genes’ expression is altered in HCC samples; among these, a subset of twenty-two correlate with patients’ survival. DNA methylation correlates with eight of these genes’ expression, and Guadecitabine, a hypomethylating agent, regulates the expression of seven down-regulated and three up-regulated genes in HepG2 cells. The down-regulated genes displayed a marked decrease of euchromatin histone marks, whereas up-regulated genes displayed gain in these marks. Additionally, the expression of these genes is modulated during liver regeneration and showed similar profiles between in vitro differentiated hepatocytes and liver-derived hepatocytes. In conclusion, some components of the Ca²⁺-signaling are altered in HCC and displayed a correlation with patients’ survival. DNA methylation and HMP are an attractive target for future investigations to regulate their expression. Ca²⁺-signaling could be an important regulator of cell proliferation and differentiation in the liver.Electronic supplementary materialThe online version of this article (10.1007/s12079-020-00597-w) contains supplementary material, which is available to authorized users.