Epigenetics and Autoimmunity, with Special Emphasis on Methylation

Abstract

10Epigenetics signifies stable and heritable changes in gene expression without changes in the genetic code. There is a wealth of emerging evidence for such processes in promoting autoimmunity. The first clue is that inhibition of DNA methyl transferases (DNMTs) induces systemic lupus erythematosus (SLE) in animals. Similar immune-mediated disorders have been generated by injecting normal T cells incubated with DNMT inhibitors into healthy mice. Further, monozygotic twins display differences in DNA methylation that parallel discordances in SLE. Moreover, defects in DNA methylation characterize lymphocytes from SLE, synoviocytes from rheumatoid arthritis, and neural cells from multiple sclerosis patients. It has also been shown that DNA hypomethylation of T and B cells correlates with reduced DNMT efficacy and histone acetylation in SLE. Once a gene promoter has been demethylated, the gene recovers its capacity to be transcribed, e.g., genes for cytokines, activation receptors on cells, and endogenous retroviruses. This outcome has been associated with a blockage of the Erk pathway and/ or a growth arrest at the G0/G1 interface of the cell cycle. Of importance is the fact that these changes can be reversed.

Abnormal Epigenetic Modifications in Peripheral T Cells from Patients with Abdominal Aortic Aneurysm Are Correlated with Disease Development

“…Unlike genetic alterations - which are permanent and affect all descendant cells - epigenetic modifications are cell-type-specific. For example, defective DNA methylation is present in T and B lymphocytes involved in SLE, in synoviocytes in rheumatoid arthritis and in neural cells in multiple sclerosis patients [19]. Promoter demethylation returns the capacity for gene transcription, and global DNA demethylation enhances the expression of multiple cytokines, receptors and endogenous retroviruses.…”

cAMP-responsive Element Modulator (CREM)α Protein Induces Interleukin 17A Expression and Mediates Epigenetic Alterations at the Interleukin-17A Gene Locus in Patients with Systemic Lupus Erythematosus

“…This is the first report to show that the IL17A gene in human T cells from SLE patients is subject to epigenetic remodeling at various levels. Histone modifications such as acetylation, methylation, and phosphorylation rearrange the structure of nucleosomes and thereby regulate the genomic accessibility for transcription factors (37). Acetylation of histone H3 contributes to transcriptional activation whereas trimethylation of H3K27 represses gene transcription.…”

cAMP-responsive Element Modulator (CREM)α Protein Signaling Mediates Epigenetic Remodeling of the Human Interleukin-2 Gene

“…Modifications to histone tails, such as acetylation, methylation, and phosphorylation, are responsible for changes in the organization of nucleosomes, thus regulating genomic accessibility for transcription factors and RNA polymerases (25). Generally, histone acetylation is associated with transcriptional activation whereas histone trimethylation reduces transcriptional activity.…”