Epigenetics is the regulation of gene expression through alterations in DNA or associated factors (other than the DNA sequence). These factors control the diverse manifestations of diseases. Insights ...into epigenetic modification may lead to new therapies for common diseases.
In this Perspective, we synthesize past and present observations in the field of epigenetics to propose a model in which the epigenome can modulate cellular plasticity in development and disease by ...regulating the effects of noise. In this model, the epigenome facilitates phase transitions in development and reprogramming and mediates canalization, or the ability to produce a consistent phenotypic outcome despite being challenged by variable conditions, during cell fate commitment. After grounding our argument in a discussion of stochastic noise and nongenetic heterogeneity, we explore the hypothesis that distinct chromatin domains, which are known to be dysregulated in disease and remodeled during development, might underlie cellular plasticity more generally. We then present a modern portrayal of Waddington's epigenetic landscape through a mathematical formalism. We speculate that this new framework might impact how we approach disease mechanisms. In particular, it may help to explain the observation that the variability of DNA methylation and gene expression are increased in cancer, thus contributing to tumor cell heterogeneity.
Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic ...disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention.
It is becoming clear that epigenetic changes are involved in human disease as well as during normal development. A unifying theme of disease epigenetics is defects in phenotypic plasticity--cells' ...ability to change their behaviour in response to internal or external environmental cues. This model proposes that hereditary disorders of the epigenetic apparatus lead to developmental defects, that cancer epigenetics involves disruption of the stem-cell programme, and that common diseases with late-onset phenotypes involve interactions between the epigenome, the genome and the environment. Increased understanding of epigenetic-disease mechanisms could lead to disease-risk stratification for targeted intervention and to targeted therapies.
Epigenetics as a mediator of plasticity in cancer Feinberg, Andrew P; Levchenko, Andre
Science (American Association for the Advancement of Science),
02/2023, Letnik:
379, Številka:
6632
Journal Article
Recenzirano
The concept of an epigenetic landscape describing potential cellular fates arising from pluripotent cells, first advanced by Conrad Waddington, has evolved in light of experiments showing ...nondeterministic outcomes of regulatory processes and mathematical methods for quantifying stochasticity. In this Review, we discuss modern approaches to epigenetic and gene regulation landscapes and the associated ideas of entropy and attractor states, illustrating how their definitions are both more precise and relevant to understanding cancer etiology and the plasticity of cancerous states. We address the interplay between different types of regulatory landscapes and how their changes underlie cancer progression. We also consider the roles of cellular aging and intrinsic and extrinsic stimuli in modulating cellular states and how landscape alterations can be quantitatively mapped onto phenotypic outcomes and thereby used in therapy development.
Motivation: The recently released Infinium HumanMethylation450 array (the ‘450k’ array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ∼450 000 loci across a range of genomic ...features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost-effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years.
Results: Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods.
Availability and implementation:
http://bioconductor.org/packages/release/bioc/html/minfi.html.
Contact:
khansen@jhsph.edu; rafa@jimmy.harvard.edu
Supplementary information:
Supplementary data are available at Bioinformatics online.
Epigenetics, the study of non-DNA sequence−related heredity, is at the epicenter of modern medicine because it can help to explain the relationship between an individual's genetic background, the ...environment, aging, and disease. It can do so because the epigenetic state varies among tissues and during a lifetime, whereas the DNA sequence remains essentially the same. As cells adapt to a changing internal and external environment, epigenetic mechanisms can remember these changes in the normal programming and reprogramming of gene activity. The common disease genetic and epigenetic (CDGE) model provides an epidemiologic framework that can incorporate epigenetic with genetic variation in the context of age-related susceptibility to disease. Under CDGE, the epigenetic program can modify the effects of deleterious genes or may be influenced by an adverse environment. Thus, including epigenetics into epidemiologic studies of human disease may help explain the relationship between the genome and the environment and may provide new clues to modifying these effects in disease prevention and therapy.
This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of 'tumour progenitor genes'. These genes are epigenetically disrupted at the earliest stages ...of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: 'epigenetic mediators', corresponding to the tumour progenitor genes suggested earlier; 'epigenetic modifiers' of the mediators, which are frequently mutated in cancer; and 'epigenetic modulators' upstream of the modifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.
Single-cell omics is transforming our understanding of cell biology and disease, yet the systems-level analysis and interpretation of single-cell data faces many challenges. In this Perspective, we ...describe the impact that fundamental concepts from statistical mechanics, notably entropy, stochastic processes and critical phenomena, are having on single-cell data analysis. We further advocate the need for more bottom-up modelling of single-cell data and to embrace a statistical mechanics analysis paradigm to help attain a deeper understanding of single-cell systems biology.
Epigenome-wide association studies of disease widely use DNA methylation measured in blood as a surrogate tissue. Cell proportions can vary between people and confound associations of exposure or ...outcome. An adequate reference panel for estimating cell proportions from adult whole blood for DNA methylation studies is available, but an analogous cord blood cell reference panel is not yet available. Cord blood has unique cell types and the epigenetic signatures of standard cell types may not be consistent throughout the life course. Using magnetic bead sorting, we isolated cord blood cell types (nucleated red blood cells, granulocytes, monocytes, natural killer cells, B cells, CD4
+
T cells, and CD8
+
T cells) from 17 live births at Johns Hopkins Hospital. We confirmed enrichment of the cell types using fluorescence assisted cell sorting and ran DNA from the separated cell types on the Illumina Infinium HumanMethylation450 BeadChip array. After filtering, the final analysis was on 104 samples at 429,794 probes. We compared cell type specific signatures in cord to each other and methylation at 49.2% of CpG sites on the array differed by cell type (F-test P < 10
−8
). Differences between nucleated red blood cells and the remainder of the cell types were most pronounced (36.9% of CpG sites at P < 10
−8
) and 99.5% of these sites were hypomethylated relative to the other cell types. We also compared the mean-centered sorted cord profiles to the available adult reference panel and observed high correlation between the overlapping cell types for granulocytes and monocytes (both r=0.74), and poor correlation for CD8
+
T cells and NK cells (both r=0.08). We further provide an algorithm for estimating cell proportions in cord blood using the newly developed cord reference panel, which estimates biologically plausible cell proportions in whole cord blood samples.
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