Epigenetics of autoimmune disorders is the role that epigenetics (heritable changes that do not involve alterations in DNA sequences) play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.
Whether someone develops an autoimmune disorder is dependent on genetics as well as environmental factors. Some families show genetic predisposition for these conditions, however genetics alone is often not sufficient to explain whether someone will develop an autoimmune condition. Smoking, stress, and diet can produce epigenetic modifications to the genome that alter the regulation of immune system-specific genes leading to the onset of these conditions.
The main mechanisms of epigenetic alterations are DNA methylation, histone modifications, and regulation by non-coding RNAs. These epigenetic changes regulate the expression of genes, including those involved in the immune system, and therefore these modifications play a role in the onset and symptoms of different systemic and local autoimmune diseases.
Epigenetic mechanisms DNA methylation DNA methylation is an epigenetic modification that interferes with transcription and causes decreased levels of gene expression. The addition of methyl groups to DNA nucleotides inhibits transcription by creating a surface that transcription factors are unable to bind. Additionally, DNA methylation recruits methyl-CpG-binding domain proteins that signal for the formation of co-repressor complexes that alter chromatin structure and further inhibit transcription. A hypermethylated DNA state is associated with gene silencing while a hypomethylated DNA state is associated with increased levels of transcription and gene expression. DNA methylation is carried out by DNA methyltransferases (DNMTs) which attach methyl groups at the 5th position of a cytosine nucleotide. In vertebrates, gene expression is modulated in particular by methylation within a region of the genome known as a CpG island, a region near a gene's promoter that contains a high percentage of cytosine and guanine nucleotides. DNA demethylation is carried out by ten-eleven translocation (TET) enzymes which convert 5-methylcytosine (5mC) into hydroxymethylcytosine (5hmC), leading to the demethylation of that segment of DNA and an increase in gene expression. TET inhibitors have been identified as potential treatments for autoimmune diseases, particularly rheumatic ones.
Histone modification Histone modification, resulting in conformational changes to protein binding sites, is involved in autoimmune disorders. Histone acetylation leads to increased transcription by promoting gene expression. Primarily, histone acetylation increases gene expression by reducing cross-linking between neighboring nucleosomes. Preventing this interaction between adjacent nucleosomes serves as a key driver of condensation. Additionally, histone acetylation also interferes with the electrostatic interaction between positively charged histones and negatively charged DNA by neutralizing some of the positive charges on the histone tails. This helps further promote gene expression by causing the histones to relax their grip on the DNA. Although acetylation helps to make DNA more accessible for transcription, histone acetylation's ability to make chromatin remodeling more likely to occur is an extremely important part in its ability to alter gene expression. This remodeling allows condensed heterochromatin to transform into a more relaxed euchromatin which is associated with higher levels of gene transcription.
Acetylation also functions as a way of recruiting transcription factors that promote gene expression. One way this recruitment occurs is through the activity of TAF1 (TATA-box binding protein associated factor 1) which contains a double bromodomain and can detect very low levels of histone acetylation. TAF1 detects acetylation and then recruits transcription factors to the acetylated region. Acetylation frequently occurs near promoter regions and is recognized by TAF1 which tethers TFIID to this region in order to increase the likelihood of TFIID locating the core promoter and initiating transcription. TAF1 also behaves as a HAT (histone acetyltransferase) and acetylates nearby histones at an increased frequency. Acetylation also prevents the addition of repressive marks to the DNA.
Normally, histone deacetylases (HDACs) serve to remove acetyl groups from the lysine residue of the histone causing a decrease in gene expression. HDAC activity is involved in the pathology of autoimmune diseases, such as in rheumatoid arthritis where HDAC activity is low in the synovial tissues. Histone methylation is also implicated in autoimmune disorders. This can be by inhibition of histone methylation such as in systemic sclerosis or by elevated histone methylation at certain gene loci in Type I diabetes.
Histone modification can give rise to rheumatic, endocrinological, and gastrointestinal autoimmune disorders. Histone modification leads to either activation or repression of gene expression depending on the disorder. Suberanilohydroxamic acid (SAHA), also known as Vorinostat, inhibits the activity of HDACs. Vorinostat has shown promise as a treatment for immune system dysfunctions. Vorinostat, by inhibiting HDACs, can treat cutaneous T cell lymphoma. Though epigenetics-based treatments for autoimmune rheumatic disorders does not exist yet, Vorinostat's function in treating T cell lymphoma is a basis for a path to epigenetics-based treatment of autoimmune rheumatic disorders.
Non-coding RNAs
Micro-RNAs (miRNAs) Micro-RNAs (miRNAs) are small RNA fragments, 18–23 nucleotides in length, that act to regulate gene expression post-transcriptionally. miRNAs play a critical role in modulating the immune response since they influence whether or not the mRNA transcribed from specific immune related genes will go on to be translated into protein or not. Alteration of different miRNA levels is associated with autoimmune disease pathogenesis and symptoms. Depending on the disorder, upregulation or downregulation of a specific type of miRNA may be observed. miRNAs negatively regulate gene expression by binding to complementary mRNA sequences within the 3' untranslated region (3' UTR). This process of miRNA activity begins with the synthesis of pri-miRNA in the nucleus by RNA polymerase II which is then converted into pre-miRNA. This pre-miRNA exits the nucleus and is cut by Dicer into a double stranded RNA with one of the strands binding to the RISC complex. This binding leads to the association of the miRNA with its target mRNA sequence and encourages the degradation of the mRNA or represses translation of the mRNA, decreasing gene expression. miRNA can also affect gene expression via the binding of RNA-induced transcriptional silencing (RITS) complex. The binding of the RITS complex to miRNA allows for post-transcriptional histone modifications such as methylation to be made further altering gene expression.
Long non-coding RNAs (lncRNAs) Long non-coding RNAs have also been identified as playing an important role in gene expression. These lncRNAs are RNAs that are more than 200 nucleotides in length but are not transcribed into any functional protein. They have been identified to play a role in the epigenetics of diseases such as discoid lupus erythematosus and rheumatoid arthritis. One method by which lncRNAs regulate gene expression is through the process of X inactivation which functions as a way to provide dosage compensation. In X-inactivation, Xist (X-inactive specific transcript) lncRNA is transcribed and coats the Xi chromosome that will be inactivated, beginning the process of chromosome condensation and repression of genes on that X chromosome. Still, more research is needed to further understand the mechanisms these lncRNAs use in order to regulate gene expression.
Systemic autoimmune diseases Systemic autoimmune diseases are those that effect multiple organ systems rather than targeting a single type of tissue or organ system.
Rheumatoid arthritis (RA) Rheumatoid arthritis is a degenerative autoimmune disease that causes damage and inflammation to a patient's joint and can affect bodily systems involving the heart, lungs, nerves, eyes, bones, and skin. Global DNA hypomethylation is a hallmark of Rheumatoid Arthritis and is observed in the early stages of this disease, when joint degeneration begins. Those who suffer from RA have a global decreased level of methylation on many DNA promoter regions including those associated with normal immune system and joint function. This overexpression from hypomethylation is observed in various genes such as ITGAL, CD40LG, PRF1, and more. Taking a closer glance at those who suffer from RA, it can be observed that within the synovial cells, there is a level of hypomethylation which is proposed to cause the expression and overproduction of the cytokines which perpetuate the inflammatory response causing inflammation within the synovial fluid, which is the fluid that exists between the joints. Typically, healthy joints have a thin layer of synovial tissue that lines the cavities of the joints. However, as an increase number of immune cells begins to penetrate the tissue, the synovial tissue begins to form a thick lining layer that consists of different macrophages and synovial cells. Hypomethylation of CD40LG, which will make the T-cells within the immune response, can lead to T-cell overexpression and becomes a contributing factor to how Rheumatoid Arthritis functions within an inflammatory response. Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, as well as decreased methylation at the Il6 and ERa promoter. TET proteins, more specifically the TET1-TET3 enzymes and TET2 in T cells can demethylate DNA which helps to set and clarify the early stages of RA. The RA development from demethylation of histones in the patient can lead to expression of high levels of IL-6 which causes destruction in the joints. miRNAs also play an important part in rheumatoid arthritis development as well, particularly the upregulation of miRNA-146a and miRNA-150. Although more research is needed, lncRNAs have been implicated to play a role in this disease since current treatments used for this disorder show altered expression of 85 different lncRNAs in RA patients on tocilizumab and adalimumab.