The oligodendrocytes are a key to maintain the central nervous system by providing support and insulation to axons.
go Stem cell commitment to oligodendrocyte is modulated by histone acetylation levels since deacetylation promotes oligodendrocyte differentiation, while acetylation is associated with inhibition of differentiation. Resveratrol, a SIRT1 activator, has shown promising results when tested in EAE mice, preventing neuronal loss during optic neuritis, providing neuroprotection, and a demonstrated secondary benefit in clinical dysfunction [ ]. These results have also been shown using other SIRT1 activators. However, these treatments did not prevent inflammatory cell infiltration in these tissues.
Histone acetylation also plays a direct role on immune response. For example, IL expression is regulated by the T cell transcription factor TCF1 through the acetylation of histones.
Modification of histone acetylation has emerged as therapeutic treatment for MS. In this context, HDAC inhibitors have potential therapeutic value in MS because of their anti-inflammatory and neuroprotective effects both in vitro and in vivo. For example, sodium phenylacetate SPA suppresses neurological damage in mice pretreated with myelin basic protein MBP —primed T-cells [ ].
Several a histone deacetylase inhibitors have been used in the EAE mouse model as potential drugs for human treatment. Trichostatin A TSA treatment after myelin oligodendrocyte glycoprotein MOG immunization reduces inflammation, cell infiltration, demyelination, and neuronal loss in the spinal cord and ameliorates the disability of EAE relapse [ ].
Studies using inhibitors of histone demethylase in EAE model are less extended. Histone modifying drugs are promising MS therapies based on their properties to modulate overactive immune system and neuroprotective pathways to prevent CNS damage. IBD is the term used to describe disorders that involve chronic inflammation of the digestive tract. In addition to the gastrointestinal tract inflammation, so-called extraintestinal symptoms are common, affecting the joints, eyes, skin, and liver. Active inflamed tissue from ulcerative colitis patients is characterized by global DNA hypomethylation compared to patients with inactive ulcerative colitis or to healthy individuals [ ].
The higher turnover of colonic epithelial cells leads to an increase in DNA methylation in tumor-suppressor genes and a decrease on pro-tumorigenic elements which could lead to genome instability and cancer development [ ]. There are fewer studies regarding histone methylation and acetylation in IBD.
Histone acetylations such as H4K8ac and H4K12ac were found in inflamed mucosa compared with non-inflamed mucosa from mice treated with sodium dextran sulfate DSS and 2,4-trinitrobenzene sulfonic acid TNBS. Furthermore, HDAC9 inhibition prevents colitis in mice as a consequence of an increase in both, Treg frequency and its suppressive function [ ]. An interesting perspective when talking about IBD is the effect of the gut microbiota. In the same line, ulcerative colitis patients treated with microbiota therapy with Roseburia , a bacterium known to produce butyrate, an HDAC inhibitor, showed a positive effect in patient recovery by reducing inflammatory cytokines production [ ].
Butyrate increases H3 acetylation on Foxp3 loci, the master transcription factor required for Treg cell differentiation [ ]. In addition, butyrate might modulate the function of intestinal macrophages since macrophages treated with butyrate downregulated LPS induced IL and IL-6 cytokine expressions [ ]. Thus, the commensal microbiota may play a beneficial role in IBD treatment via epigenetic regulation of gene expression.
Epigenetics and Pathology: Exploring Connections Between Genetic Mechanisms and Disease Expression - CRC Press Book. Buy Epigenetics and Pathology: Exploring Connections Between Genetic Mechanisms and Disease Expression on lapetela.gq ✓ FREE SHIPPING on.
During the recent years, several studies have focused on a better understanding of epigenetic processes as well as its connection with biological processes such as immune response and inflammation Figure 4. Currently, many epigenetic studies are being carried out in cells of the immune system related to the inflammasome such as DCs, macrophages, and lymphocytes.
Most of those studies are related to the epigenetic mechanisms associated to the development, differentiation, and function of these cells, leading to a better knowledge about how epigenetics of the immune system relates to its function in pathogenesis. The interactions between genetic and epigenetic factors significantly contribute to inflammation and autoimmune diseases. Epigenetic research has grown and is providing new insights into inflammatory autoimmune diseases, insight that will allow us to explain the etiology of these diseases.
Furthermore, studies on epigenetic changes could lead us to understand disease progression and to identify future markers for therapy. Although further studies are needed to address the potential of epigenetic factors to act as biomarkers and drug targets, epigenetic enzymes are the current target of drug development and new therapeutic trials. Epigenetic analyses, including DNA methylation and histone modifications, require a large number of cells making these studies difficult.
Recent advances in technologies such as in single-cell analysis provide a new solution to this problem. Nevertheless, an important issue to be addressed is the limited information obtained so far for several cell subsets, specifically those with small representation within the immune system. As conclusion, although some important advances have been achieved in our understanding on the epigenetics of immune cells, inflammation, and autoimmune diseases, new technologies are required to improve our knowledge on these processes.
Epigenetics influences on the development of autoimmune diseases. Epigenetic changes on the promoter of several genes are triggered by yet unknown factors, inducing transcriptional activation or repression. These changes bring up alterations in development, differentiation, and effector function of immune cells.
All these changes result in aberrant immune responses, including increased production of proinflammatory cells and cytokines or the reduction of anti-inflammatory cells and cytokines that lead to increased inflammation and autoimmune diseases. AID activation-induced cytidine deaminase. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications.
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Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Downloaded: Abstract During recent years, numerous studies have shown that epigenetics, heritable changes that do not involve alterations in the DNA sequence, play an important role in the development, function, and regulation of the immune system as well as in the onset and progress of autoimmune diseases.
Keywords epigenetic DNA methylation histone modification autoimmunity therapy. Introduction Conrad Waddington introduced the epigenetic term in , and it was defined as the causal interactions between genes and their products that allow for phenotypic expression [ 1 ]. A brief introduction to epigenetics The classical concept of heritable information is that phenotypic characteristics are transmitted from parental cell to their offspring by genetic information [ 3 ].
Epigenetic regulation of immune cell development, function, and effector function 3. Epigenetic regulation of autoimmune diseases and the prospect of epigenetic drug as therapeutic agents Autoimmune diseases are a complex group of diseases in which each one present with a unique epidemiology, pathology, symptoms, and origin. Conclusions During the recent years, several studies have focused on a better understanding of epigenetic processes as well as its connection with biological processes such as immune response and inflammation Figure 4. Download chapter PDF. More Print chapter.
How to cite and reference Link to this chapter Copy to clipboard. Available from:. Over 21, IntechOpen readers like this topic Help us write another book on this subject and reach those readers Suggest a book topic Books open for submissions. More statistics for editors and authors Login to your personal dashboard for more detailed statistics on your publications. Access personal reporting. A variety of compounds are considered as epigenetic carcinogens —they result in an increased incidence of tumors, but they do not show mutagen activity toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded.
Examples include diethylstilbestrol , arsenite , hexachlorobenzene , and nickel compounds. Many teratogens exert specific effects on the fetus by epigenetic mechanisms. Melanoma is a deadly skin cancer that originates from melanocytes. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes.
Prostate cancer kills around 35, men yearly, and about , men are diagnosed with prostate cancer per year, in North America alone. Genomic methylation patterns have been associated with invasive cervical cancer. Recent studies have shown that the mixed-lineage leukemia MLL gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.
There are about 15, new cases of sarcoma in the US each year, and about 6, people were projected to die of sarcoma in the US in Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma,  or of LSD1 in several sarcomas,  inhibits tumor cell growth in these sarcomas. Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team.
Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells. Since bisulfite sequencing is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing. Popular approaches for determining histone modification profiles in cancerous versus healthy cells include: . Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately.
Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example, MGMT is an enzyme that reverses the addition of alkyl groups to the nucleotide guanine. Epigenetic biomarkers can also be utilized as tools for molecular prognosis. In primary tumor and mediastinal lymph node biopsy samples, hypermethylation of both CDKN2A and CDH13 serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.
Epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer. Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs.
Drugs that specifically target the inverted methylation pattern of cancerous cells include the DNA methyltransferase inhibitors azacitidine   and decitabine. From Wikipedia, the free encyclopedia. Main article: DNA methylation in cancer. PLoS Genetics. Disease Markers.
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Cancer Communications. Clowes Memorial Award Lecture". Cancer Res. In Chen C ed. Trends in Biochemical Sciences. International Journal of Genomics. Current Colorectal Cancer Reports. Bibcode : PNAS.. FEBS Letters. Molecular and Cellular Biology. Nucleic Acids Research. Genome Integrity. Molecular Aspects of Medicine. Clark Chen Ed. Clark Chen ed. The Journal of Biological Chemistry.
Molecular Cancer Research. MCR inactive BJU International. Project: Targeting gene expression to treat disease. Problem: Efforts to modify the CRISPR-Cas9 system to target specific methylation marks and histone modifications without cutting DNA have been relatively successful in cell culture, but translating the work to live animals has proven challenging. Solution: Belmonte and his team set out to create a smaller epigenetic editor. They had a radical idea: Why not split the editor in two?
One part, carried by an adeno-associated virus, would contain the Cas9 enzyme, and the other, carried by a second adeno-associated virus, would ferry the guide RNAs and gene switches. The two parts would work together to turn gene expression up or down. E15, Upregulating these genes compensated for disease-associated genetic mutations, improving symptoms in the mouse models of those diseases.
The researchers also used the tool to overexpress certain long noncoding RNAs and genes rich in guanine and cytosine, which are challenging to sequence, revealing their biological functions. Project: Blocking gene expression to lower cholesterol. Mice that received the gene-expression—blocking therapy had lower LDL cholesterol levels than mice that received a sham treatment.
An antibody drug that inhibits this protein to boost LDL removal has already been approved for treating familial hypercholesterolemia, a genetic disease in which the PCSK9 protein fails to remove LDL from the blood. Other therapies in development aim to inhibit the gene using synthetic oligonucleotides or gene editing. Because so much work has been done on PCSK9 and its connection with cholesterol, scientists know a lot about its expression.
That foundation is helpful for building an epigenome editor that modulates it, says Gersbach.