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Sandbox of Emily Breach, Aamani Pillutla, Oliver Myers

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Epigenetics plays a major role in the onset of autoimmune diseases like multiple sclerosis, lupus, and rheumatoid arthritis. Developing a better understanding of these conditions in the context of epigenetics offers hope in potential development of new therapeutic treatment options^[1]. In this article, we would explore how histone modifications such as methylation and acetylation of the genome produce the phenotypes of these diseases. Interestingly, recent research has shown that across the genomes of those with these conditions, they share similar modifications in the non-coding region of the RNA rather than the portion that is transcribed and translated into a protein^[1]. As well as discussing these commonalities across disorders, we could next explore how epigenetics plays a role in the onset of these diseases since they have both a genetic and an environmental component. We would explore how the epigenome plays as an intermediary in regulating the way that the immune system responds to environmental hazards such as UV rays and oxidative stress^[2] and then venture into the specific of each individual condition. As a start, I have listed out 12 common autoimmune diseases, particularly ones relating to endocrinology, neurology, and connective tissue. Under each disease heading we will explore which epigenetic modifications are associated with these diseases and how they are casual with their associated symptoms. We will also explore what types of treatments currently exist for these conditions briefly and what way treatment is going towards in terms of therapeutics that target the epigenome. I'm very open to any feedback from those interested in this project. Under each section I have cited a few modifications associated with each of these conditions and have included review articles that we can use to write up each section. This would be an awesome group to join if you're interested in pursuing medicine or if you have an autoimmune disease like myself and would like to better understand your condition!

What would we write about?: We we would start with a section briefly brushing up on epigenetic modulation and how the immune system works such as CD4 T cells and innate vs acquired immunity and how this is modulated by the epigenome^[3]. We'd then discuss current technologies being utilized to study this and go into how in the past, researchers have had difficulty with identifying the SNP mutations in the DNA responsible for these conditions as well as elucidating how these mutations alter normal cellular pathway and lead to pathogenesis and then discuss how research using GWAS (genome-wide association studies) has begun to utilize computer modeling to sift through this data and identify specific casual mutations. For example, Farh et al utilized a computational model to identify SNPs for 21 different auto immune diseases and after looking at loci associated with autoimmunity, they identified 12% of causal SNPs for these conditions^[4]. We can also describe how we are advancing as far as our understanding of epigenetic modifications in the genome and how this is effecting the way these conditions are being treated. After this, we would go into types of modifications and discuss ones common across a group of conditions. Here, we can discuss how human leukocyte antigen(HLA) is heavily linked to the pathogenesis of autoimmune disorders as well, so here I would also include a general discussion of how this plays a key role, as well as explore how non-HLA genes such as IRF8, OLIG3/TNFAIP3, IL23R, IL2RA, IRF8, IRF5, PTPN22, ICAM3, STAT4, and BANK1 are involved across different conditions^[2] . Lastly under each disease we will go into defining the diseases, modifications specific to these diseases and the causal role they play in the pathogenesis and potential treatments in relation to the epigenome. If members prefer, this article can instead be broken down instead by types of condition like the epigenetic of connective tissue autoimmune diseases and epigenetic of endocrinological autoimmune etc.

Epigenetics of Autoimmune Disorders

Autoimmune disorders are a diverse class of diseases characterized by a person's immune system attacking their healthy cells. Autoimmune diseases include Lupus, Rheumatoid Arthritis, and Multiple Sclerosis to name a few.^[5] Many different factors can account for the onset of autoimmune disorders, however there is a large epigenetic component particularly regarding how alterations in methylation patterns plays a role in these diseases' pathology. Additionally, dysregulation of non-coding RNA and histone modification are key players in exploring the epigenetics underlying these diseases^[2] . Here also discuss evidence comparing prevalence of the diseases compared between dizygotic and monozygotic twins^[2] . Also discuss how/why autoimmune diseasses are more common in women ^[6] .

Mechanisms of Epigenetic Modifications

Comment: add section describing overview of mechanisms: Use these articles!!! ^[7]^[5]^[8]^[9],

DNA Methylation

Hypomethylation, a loss of DNA methylation, particularly hypomethylation of DNA promoters is heavily associated with multiple different autoimmune disorders, specifically rheumatoid arthritis and systemic lupus erythematosus; Next discuss procainamide and hydralazine induced lupus like condition an d how this relates to hypomethylation as underlying cause of many autoimmune diseases^[4]. Here we would also discuss circRNA and how it is a regulator of methylation and the immune system and how this is tied into many autoimmune conditions^[10] Next write about hypermethylation and its role in autoimmune diseases like Type 1 Diabetes. Include research from the Farh et al paper because this is a big deal in the epigenetic research as far as identifying causal loci via GWAS and iChip analysis^[4].

#800080

Histone Modification

Recommend describing mechs more here to give better big picture ^[8]

Non-Coding RNAs

Micro-RNAs

Recommend describing mechs more here to give better big picture ^[8]

Epigenetics of 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 damages and causes inflammation in a patient’s joint. It is characterized by hypomethylation of synovial cells and CpG island hypomethylation ^{^[5]} . Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, and decreased methylation at the Il6 and ERa promoter ^{^[11].}. 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 ^[8]. This early stage is more closely observed to be the formation by the TET proteins to cause aberrant global DNA hypomethylation which is the start of the degenerative property and hallmark of Rheumatoid Arthritis ^[8]. Furthermore, the epigenetic nature of RA is intertwined with the chronic inflammation and significant disability of the immune system in the body that leads to the aberrant histone modifications. The RA development from demethylation of histones in the patient has been observed to express high levels of IL-6 which causes destruction in the joints ^[8].

Systemic Lupus Erythematosus(SLE)

Systemic lupus erythematosus is the most common form of lupus and is a condition in which the immune system attacks healthy bodily tissue. Hypomethylation is observed across the epigenome in those with systemic lupus. The promoter regions of many genes including ITGAL, CD40LG, and CD70 are shown to be hypomethylated as well as the 18S and 28S ribosomal gene promoters. In particular, this DNA hypomethylation is thought to alter the chromatin structure of T cells enhancing the immune and inflammatory response observed in those with this condition^[5]. Genome wide it has been shown that when comparing the epigenomes of pairs of identical twins in which one twin is afflicted by the condition and one is not, the twin's possessing the condition show global decreases in methylation of their genomes. This hypomethylation causes genes that are traditionally repressed by methylation to be overexpressed particularly in CD4+ T cells. Recently, it has been explored which causative mechanisms are responsible for this genome-wide demethylation and inhibition of DNMT1 has been identified as a potential culprit. DNMT1 is a DNA methyltransferase that conserves methylation patterns from the parent DNA strand to a new copy of DNA during DNA replication. By inhibiting DNMT1 methylation patterns are lost across DNA lines and overall hypomethylation is observed as a result. In particular, it has been observed that DNMT1 expression is lower in immune T-cells. ^[2]

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Systemic Sclerosis (SSc)

Systemic sclerosis is an autoimmune disease that causes the patient’s skin and connective tissues to tighten and harden due to the uncontrolled accumulation of Extracellular Matrix (ECM) Proteins^{^[5].} These ECM Proteins are observed to impact the patient suffering from SSc by affecting the joints and various internal organ systems, even leading to premature death in patients. hypermethylation of CpG islands in Fli1 promoter leads to the overproduction of the fibers affecting the joints and skin thickness of the person suffering from SSC Decreased levels of DNA methyltransferases (DNMTs) in SSc CD4+ T cells suggesting a correlation of this reduced Methylation leading to the progression of SSc and its inflammatory effects, however more research is mentioned to be needed to help further understand this implication^[11].

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Epigenetics of Local Dermatological Autoimmune Disorders

Discoid Lupus Erythematosus (DLE)

Discoid lupus erythematosus is the most common form of the cutaneous autoimmune condition in which the immune system attacks healthy tissue and is presented by lesions on the skin, inflammation, and rashes which can result in pigment changes and scarring of the skin even hair loss for those impacted. Here we will explore how differential expression of lncRNAs and circRNAs identified in a study by Xuan et alter the mucosa a key part in this disease^[10]. In said study, many transcripts for DLE were found to be expressed in affected tissue incRNAs and to a significant extent but lesser circRNAs were expressed as compared to a control nonaffected tissue. The pattern of expressed incRNAs and circRNAs helps to discriminate against affected tissue of DLE and healthy nonaffected tissues establishing a useable pattern for reference^[10] . Furthermore, the IncRNAs were found to be present in both X and also Y chromosomes giving reference to their inheritability and non-sex selective nature. It was found that through analysis of the function and expression of lncRNA that IncRNAs had various correlations with Il19, CXCL1, CXCL11, and TNFSF15 which all are related to an immune response helping to identify the pathway in which DLE is manifested genetically by the abnormal expression of IncRNA . Another key portion of the Xuan et alter study was the identification of STAT4 as being a key Transcription factor responsible for influencing the regulation of many target genes involved in DLE but this needs to be further investigated as mentioned in the article ^[10].

Psoriasis

Psoriasis is an autoimmune skin condition in which skin cells are generated too rapidly leading to a buildup of these cells producing scaly red patches on the patient's body. Keratinocyte hyper-proliferation, which leads to an overproduction of keratin, and T cell dysregulation play a key role in this condition. Decreased DNA methylation is observed in patients with psoriasis, particularly in CD4+ T cells. Additionally, miRNA dysregulation of miRNA-203, miRNA-31, miRNA-146a, and miRNA-210 is prevelant ^[3]. Acetylation also plays an important part in this disease and it has been shown that patient with psoriasis demonstrate abnormal expression of HDACs and HATs. HDAC-6 is hyper-methylated in CD4+ T-cells and HDAC-1 levels are shown to be increased in epidermal cells of those with psoriasis^[8]. SIRT1 has been identified as a gene involved in negative regulation of keratocyte proliferation and it plays an important role in inhibiting E2F1 activity in order to prevent abnormal cellular proliferation. In psoriasis, HDAC SIRT1 is more heavily expressed leading to increased keratocyte proliferation. HDAC inhibitors show promise as a potential treatment of psoriasis as well as many other inflammatory autoimmune disorder ^[12].

Sjogren's Syndrome

Sjorgen's syndrome is a dermatological autoimmune disorder that causes a decreased function of the lacrimal and salivary glands. In terms of research on the innate immune system, it is characterized by over expression of certain miRNAs in salivary glands, in particular miRNA-16a and miRNA-146a ^[5]^[8]. Of the miRNAs identified to play a role in this diseases, miRNA-16a role in pathogenesis of this condition has been elucidated. miRNA-16a levels play an important role in phagocytosis by monocytes, white blood cells that target and remove infected cells. In Sjorgen's patients, there is an over expression of this miRNA leading to increased ingestion by these monocytes and targeting of this over-expression is thought to hold potential in treatment of this disease ^[8]. As described previously, Sjorgen's targets the salivary gland, particularly its epithelial cells which are show to be hypomethylated. This hypomethylation is hypothesized to be linked to activity by B cells since usage of a B cell depleting antibody has been shown to restore this methylation^[8]. Epigenetic alterations in CD4 and T-cells in the immune system are also observed in this condition. Specifically, research has linked a decrease in expression of FOXP3 gene as well as CD70 promoter region hypomethylation to the development of Sjogren's syndrome ^[3].

Epigenetics of Local Endocrinological Autoimmune Disorders

Graves' Disease

Graves’ disease is an autoimmune disease involving thyrotoxicosis, in which the body is affected by the overproduction of thyroid hormone, a quality termed hyperthyroidism. Like Hashimoto’s thyroiditis, Graves’ disease is qualified as an autoimmune thyroid disease. The epigenetic processes involved in Hashimoto’s thyroiditis, namely the modification of histone methylation in Tg and skewed X chromosome inactivation, are also involved in Graves’ disease. The viral infection possibility mentioned in reference to Hashimoto’s thyroiditis also applies to Graves’ disease.^[6] In the specific case of Graves’ disease, discoveries have been made showing involvement of abnormal DNA methylation in certain CpG sites leading to interferon signaling and other immune system-related processes in cases of Graves’ disease. In fact, Graves’ disease patients have exhibited hypomethylation in CpG sites in certain T cells, indicating the implication of DNA hypomethylation in the pathophysiology of Graves’ disease.^[13]

Hashimoto's Thyroiditis

Hashimoto's thyroiditis is an endocrine disease in which a patient’s immune system attacks their thyroid gland. Hashimoto’s thyroiditis usually manifests via hypothyroidism, which is characterized by “lymphocytic infiltration of the thyroid and the production of thyroid autoantibodies”^[6]. Research suggests a strong genetic susceptibility when it comes to autoimmune thyroid diseases like Hashimoto’s thyroiditis, and an epigenetic involvement in the pathology of Hashimoto’s thyroiditis. In association with autoimmune thyroid diseases such as Hashimoto’s thyroiditis, a change in histone methylation patterns in the thyroglobulin (Tg) promoter has been found in a genetic variant, wherein Tg is a thyroid-specific gene. In specific, the transcription factor IRF-1 binds to the Tg promoter exclusively only when the disease-associated variant is present. This binding of IRF-1 to Tg is impacted by modulations in histone methylation patterns. Something of note here is that in the Tg promoter, the susceptibility allele allows the binding of IRF-1 in the case of a viral infection, pointing to a potential environmental factor on the development of Hashimoto’s thyroiditis, rather than attributing epigenetic modifications restrictively to genetic sources.^[6] In addition to histone methylation, skewed X chromosome inactivation has been found to be implicated in autoimmune thyroid diseases (specifically Hashimoto’s thyroiditis and Graves’ disease), therefore indicating that the level of X chromosome inactivation in females is an important factor in the risk of developing autoimmune thyroid diseases^[14].

Type I Diabetes

Type I diabetes is an endocrinological disease in which the immune system’s T cells attack the beta cells of the pancreas, disrupting the production of insulin. Type I diabetes is characterized by global hypermethylation^[5]. The demethylation of certain proteins is implicated in Type I diabetes such as HOXA9, a transcription factor whose demethylation has been reported in Type I diabetes. Additionally, increased DNA methylation in the Foxp3 promoter region has been observed in Type I diabetes. The increased DNA methylation of the Foxp3 promoter region leads to a reduction in the frequency of regulatory T cells, which suppress immune responses in the body, in the blood of Type I diabetics^[11]. Increased DNA methylation variability in immune effector cells in Type I diabetes has shown the involvement in DNA methylation in other processes related to Type I diabetes’ pathogenesis as well^[15].

Epigenetics of Local Gastrointestinal Autoimmune Disorders

Celiac Disease

Celiac disease is a disease in which the small intestine is damaged in those whose bodies are unable to process gluten. Celiac disease is an autoimmune disorder in which exposure to glutinous foods like wheat and rye is the primary environmental factor. Several epigenetic mechanisms have been found to be implicated in Celiac disease. A high rate of DNA methylation of CpGs contributes to the development of small bowel adenocarcinomas, which are malignant tumors, in individuals with Celiac disease. Furthermore, unusual methylation in the genes involved in the core NF-κB pathway is implicated in the pathogenesis of Celiac disease. There are also allele-specific gene methylations that impact phenotype in such a way that it can lead to Celiac disease, thus involving allele-specific methylation in Celiac disease predisposition. Additionally, an increase in histone acetylation, specifically H3K27ac, has been found in Celiac disease biopsies.^[16] Furthermore, the regulation of certain microRNAs, which are a type of non-coding RNA, differs significantly in individuals with Celiac disease compared to control individuals without Celiac disease. This significant difference was found to come in the form of downregulation of some microRNAs and upregulation of others.^[17]

Epigenetics of Local Neurological Autoimmune Disorders

Multiple Sclerosis (MS)

Multiple Sclerosis is an autoimmune disease characterized by neurodegeneration, causing damage to the myelin sheath of neurons leading to weakness, pain, and vision loss. Many miRNAs have been identified in the pathogenesis of this diseases. miRNA-326, miRNA-34a, and miRNA-155 are some of them miRNAs to be identified. miRNA-326 is upregulated in those with multiple sclerosis and is associated with flare-up in symptoms. It acts on Ets-1 which negatively regulates TH-17, a helper T cell, and its differentiation. In terms of miRNA-34a and miRNA-155 increased level of these miRNAs inhibits the CD47 signal in macrophages and leads to an increase in demyelination.^[5] It has been shown that infection with Epstein-Barr Virus, vitamin D deficiency, and smoking are associated with alteration to epigenetic markers and MS pathogenesis. Epstein-Barr Virus causes up-regulation of DNMTs, vitamin D deficiency alters expression of histone modifiers, and smoking has been shown to effect all three mechanisms of epigenome modification^[9]. Comment: another article to look at ^[7] .

Myasthenia Gravis (MG)

Myasthenia Gravis is an autoimmune disease-causing weakness and dysfunction in the affected patient’s skeletal muscles related to extensive neurological damage. It has been found in individuals who have Myasthenia Gravis have significantly higher levels of methylation in the CTLA-4 region and higher levels of expression of AchR-Ab and also E-Ach for those affected. The expression of CTLA-4 region is associated with the potential inhibition of the immune system in those affected by MG and the expression of the CTLA-4 generating cytokines regulating both AchR-Ab and E-Ach need further exploration for their mechanism of action^[18]. Look for more mechanisms for the regulation of AchR-Ab and E-Ach and then expand on the impact of methylation of the CTLA-4 region^[18].

COMMENTS

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References

^ ^a ^b Brown, Chrysothemis C.; Wedderburn, Lucy R. (2015-03). "Mapping autoimmune disease epigenetics: what's on the horizon?". Nature Reviews Rheumatology. 11 (3): 131–132. doi:10.1038/nrrheum.2014.210. ISSN 1759-4790. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b ^c ^d ^e Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. 74: 118–138. doi:10.1016/j.jaut.2016.06.020. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b ^c Jokkel, Zsofia; Piroska, Marton; Szalontai, Laszlo; Hernyes, Anita; Tarnoki, David Laszlo; Tarnoki, Adam Domonkos (2021-01-01), Li, Shuai; Hopper, John L. (eds.), "Chapter 9 - Twin and family studies on epigenetics of autoimmune diseases", Twin and Family Studies of Epigenetics, Translational Epigenetics, vol. 27, Academic Press, pp. 169–191, doi:10.1016/b978-0-12-820951-6.00009-0, ISBN 978-0-12-820951-6, retrieved 2022-02-27
^ ^a ^b ^c Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang; Kleinewietfeld, Markus; Housley, William J.; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; Shishkin, Alexander A.; Hatan, Meital (2015-02-19). "Genetic and epigenetic fine mapping of causal autoimmune disease variants". Nature. 518 (7539): 337–343. doi:10.1038/nature13835. ISSN 0028-0836. PMC 4336207. PMID 25363779.{{cite journal}}: CS1 maint: PMC format (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis (2012). "Epigenetics and Autoimmune Diseases". Autoimmune Diseases. 2012: 1–16. doi:10.1155/2012/593720. ISSN 2090-0422. PMC 3318200. PMID 22536485.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c ^d Tomer, Yaron (2014-01-24). "Mechanisms of Autoimmune Thyroid Diseases: From Genetics to Epigenetics". Annual Review of Pathology: Mechanisms of Disease. 9 (1): 147–156. doi:10.1146/annurev-pathol-012513-104713. ISSN 1553-4006. PMC 4128637. PMID 24460189.{{cite journal}}: CS1 maint: PMC format (link)
^ ^a ^b Elsen, Peter J. van den; Eggermond, Marja C. J. A. van; Puentes, Fabiola; Valk, Paul van der; Baker, David; Amor, Sandra (2014-03-01). "The epigenetics of multiple sclerosis and other related disorders". Multiple Sclerosis and Related Disorders. 3 (2): 163–175. doi:10.1016/j.msard.2013.08.007. ISSN 2211-0348. PMID 25878004.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Ciechomska, Marzena; O’Reilly, Steven (2016-08-10). "Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases". Mediators of Inflammation. 2016: e9607946. doi:10.1155/2016/9607946. ISSN 0962-9351. PMC 4995328. PMID 27594771.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b Küçükali, Cem İsmail; Kürtüncü, Murat; Çoban, Arzu; Çebi, Merve; Tüzün, Erdem (2015-06-01). "Epigenetics of Multiple Sclerosis: An Updated Review". NeuroMolecular Medicine. 17 (2): 83–96. doi:10.1007/s12017-014-8298-6. ISSN 1559-1174.
^ ^a ^b ^c ^d Le, Michelle; Muntyanu, Anastasiya; Netchiporouk, Elena (2020-03). "IncRNAs and circRNAs provide insight into discoid lupus pathogenesis and progression". Annals of Translational Medicine. 8 (6): 260–260. doi:10.21037/atm.2020.03.56. PMC 7186711. PMID 32355704. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ ^a ^b ^c Wu, Haijing; Liao, Jieyue; Li, Qianwen; Yang, Ming; Zhao, Ming; Lu, Qianjin (2018-11). "Epigenetics as biomarkers in autoimmune diseases". Clinical Immunology. 196: 34–39. doi:10.1016/j.clim.2018.03.011. {{cite journal}}: Check date values in: |date= (help)
^ Zhang, P.; Su, Y.; Lu, Q. (2012-04). "Epigenetics and psoriasis: Epigenetics and psoriasis". Journal of the European Academy of Dermatology and Venereology. 26 (4): 399–403. doi:10.1111/j.1468-3083.2011.04261.x. {{cite journal}}: Check date values in: |date= (help)
^ Razmara, Ehsan; Salehi, Mehrnaz; Aslani, Saeed; Bitaraf, Amirreza; Yousefi, Hassan; Colón, Jonathan Rosario; Mahmoudi, Mahdi (2021-02-01). "Graves' disease: introducing new genetic and epigenetic contributors". Journal of Molecular Endocrinology. 66 (2): R33 – R55. doi:10.1530/JME-20-0078. ISSN 1479-6813.
^ YIN, X.; LATIF, R.; TOMER, Y.; DAVIES, T. F. (2007-09-01). "Thyroid Epigenetics: X Chromosome Inactivation in Patients with Autoimmune Thyroid Disease". Annals of the New York Academy of Sciences. 1110 (1): 193–200. doi:10.1196/annals.1423.021. ISSN 0077-8923.
^ Paul, Dirk S.; Teschendorff, Andrew E.; Dang, Mary A. N.; Lowe, Robert; Hawa, Mohammed I.; Ecker, Simone; Beyan, Huriya; Cunningham, Stephanie; Fouts, Alexandra R.; Ramelius, Anita; Burden, Frances (2016-11-29). "Increased DNA methylation variability in type 1 diabetes across three immune effector cell types". Nature Communications. 7 (1): 13555. doi:10.1038/ncomms13555. ISSN 2041-1723.
^ Gnodi, Elisa; Meneveri, Raffaella; Barisani, Donatella (2022-01-28). "Celiac disease: From genetics to epigenetics". World Journal of Gastroenterology. 28 (4): 449–463. doi:10.3748/wjg.v28.i4.449. ISSN 1007-9327. PMC 8790554. PMID 35125829.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
^ Dieli-Crimi, Romina; Cénit, M. Carmen; Núñez, Concepción (2015-11). "The genetics of celiac disease: A comprehensive review of clinical implications". Journal of Autoimmunity. 64: 26–41. doi:10.1016/j.jaut.2015.07.003. {{cite journal}}: Check date values in: |date= (help)
^ ^a ^b Fang, Ti-Kun; Yan, Cheng-Jun; Du, Juan (2018-05). "CTLA-4 methylation regulates the pathogenesis of myasthenia gravis and the expression of related cytokines". Medicine. 97 (18): e0620. doi:10.1097/MD.0000000000010620. ISSN 0025-7974. {{cite journal}}: Check date values in: |date= (help)

^[1]

^ Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11-01). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. A Comprehensive perspective on systemic lupus erythematosus. 74: 118–138. doi:10.1016/j.jaut.2016.06.020. ISSN 0896-8411.

[:0-1] Brown, Chrysothemis C.; Wedderburn, Lucy R. (2015-03). "Mapping autoimmune disease epigenetics: what's on the horizon?". Nature Reviews Rheumatology. 11 (3): 131–132. doi:10.1038/nrrheum.2014.210. ISSN 1759-4790. {{cite journal}}: Check date values in: |date= (help)

[:1-2] Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. 74: 118–138. doi:10.1016/j.jaut.2016.06.020. {{cite journal}}: Check date values in: |date= (help)

[:6-3] Jokkel, Zsofia; Piroska, Marton; Szalontai, Laszlo; Hernyes, Anita; Tarnoki, David Laszlo; Tarnoki, Adam Domonkos (2021-01-01), Li, Shuai; Hopper, John L. (eds.), "Chapter 9 - Twin and family studies on epigenetics of autoimmune diseases", Twin and Family Studies of Epigenetics, Translational Epigenetics, vol. 27, Academic Press, pp. 169–191, doi:10.1016/b978-0-12-820951-6.00009-0, ISBN 978-0-12-820951-6, retrieved 2022-02-27

[:2-4] Farh, Kyle Kai-How; Marson, Alexander; Zhu, Jiang; Kleinewietfeld, Markus; Housley, William J.; Beik, Samantha; Shoresh, Noam; Whitton, Holly; Ryan, Russell J. H.; Shishkin, Alexander A.; Hatan, Meital (2015-02-19). "Genetic and epigenetic fine mapping of causal autoimmune disease variants". Nature. 518 (7539): 337–343. doi:10.1038/nature13835. ISSN 0028-0836. PMC 4336207. PMID 25363779.{{cite journal}}: CS1 maint: PMC format (link)

[:3-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h Quintero-Ronderos, Paula; Montoya-Ortiz, Gladis (2012). "Epigenetics and Autoimmune Diseases". Autoimmune Diseases. 2012: 1–16. doi:10.1155/2012/593720. ISSN 2090-0422. PMC 3318200. PMID 22536485.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:8-6] Tomer, Yaron (2014-01-24). "Mechanisms of Autoimmune Thyroid Diseases: From Genetics to Epigenetics". Annual Review of Pathology: Mechanisms of Disease. 9 (1): 147–156. doi:10.1146/annurev-pathol-012513-104713. ISSN 1553-4006. PMC 4128637. PMID 24460189.{{cite journal}}: CS1 maint: PMC format (link)

[:10-7] Elsen, Peter J. van den; Eggermond, Marja C. J. A. van; Puentes, Fabiola; Valk, Paul van der; Baker, David; Amor, Sandra (2014-03-01). "The epigenetics of multiple sclerosis and other related disorders". Multiple Sclerosis and Related Disorders. 3 (2): 163–175. doi:10.1016/j.msard.2013.08.007. ISSN 2211-0348. PMID 25878004.

[:7-8] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Ciechomska, Marzena; O’Reilly, Steven (2016-08-10). "Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases". Mediators of Inflammation. 2016: e9607946. doi:10.1155/2016/9607946. ISSN 0962-9351. PMC 4995328. PMID 27594771.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:12-9] Küçükali, Cem İsmail; Kürtüncü, Murat; Çoban, Arzu; Çebi, Merve; Tüzün, Erdem (2015-06-01). "Epigenetics of Multiple Sclerosis: An Updated Review". NeuroMolecular Medicine. 17 (2): 83–96. doi:10.1007/s12017-014-8298-6. ISSN 1559-1174.

[:4-10] Le, Michelle; Muntyanu, Anastasiya; Netchiporouk, Elena (2020-03). "IncRNAs and circRNAs provide insight into discoid lupus pathogenesis and progression". Annals of Translational Medicine. 8 (6): 260–260. doi:10.21037/atm.2020.03.56. PMC 7186711. PMID 32355704. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[:5-11] Wu, Haijing; Liao, Jieyue; Li, Qianwen; Yang, Ming; Zhao, Ming; Lu, Qianjin (2018-11). "Epigenetics as biomarkers in autoimmune diseases". Clinical Immunology. 196: 34–39. doi:10.1016/j.clim.2018.03.011. {{cite journal}}: Check date values in: |date= (help)

[12] Zhang, P.; Su, Y.; Lu, Q. (2012-04). "Epigenetics and psoriasis: Epigenetics and psoriasis". Journal of the European Academy of Dermatology and Venereology. 26 (4): 399–403. doi:10.1111/j.1468-3083.2011.04261.x. {{cite journal}}: Check date values in: |date= (help)

[13] Razmara, Ehsan; Salehi, Mehrnaz; Aslani, Saeed; Bitaraf, Amirreza; Yousefi, Hassan; Colón, Jonathan Rosario; Mahmoudi, Mahdi (2021-02-01). "Graves' disease: introducing new genetic and epigenetic contributors". Journal of Molecular Endocrinology. 66 (2): R33 – R55. doi:10.1530/JME-20-0078. ISSN 1479-6813.

[14] YIN, X.; LATIF, R.; TOMER, Y.; DAVIES, T. F. (2007-09-01). "Thyroid Epigenetics: X Chromosome Inactivation in Patients with Autoimmune Thyroid Disease". Annals of the New York Academy of Sciences. 1110 (1): 193–200. doi:10.1196/annals.1423.021. ISSN 0077-8923.

[15] Paul, Dirk S.; Teschendorff, Andrew E.; Dang, Mary A. N.; Lowe, Robert; Hawa, Mohammed I.; Ecker, Simone; Beyan, Huriya; Cunningham, Stephanie; Fouts, Alexandra R.; Ramelius, Anita; Burden, Frances (2016-11-29). "Increased DNA methylation variability in type 1 diabetes across three immune effector cell types". Nature Communications. 7 (1): 13555. doi:10.1038/ncomms13555. ISSN 2041-1723.

[:9-16] Gnodi, Elisa; Meneveri, Raffaella; Barisani, Donatella (2022-01-28). "Celiac disease: From genetics to epigenetics". World Journal of Gastroenterology. 28 (4): 449–463. doi:10.3748/wjg.v28.i4.449. ISSN 1007-9327. PMC 8790554. PMID 35125829.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)

[17] Dieli-Crimi, Romina; Cénit, M. Carmen; Núñez, Concepción (2015-11). "The genetics of celiac disease: A comprehensive review of clinical implications". Journal of Autoimmunity. 64: 26–41. doi:10.1016/j.jaut.2015.07.003. {{cite journal}}: Check date values in: |date= (help)

[:11-18] Fang, Ti-Kun; Yan, Cheng-Jun; Du, Juan (2018-05). "CTLA-4 methylation regulates the pathogenesis of myasthenia gravis and the expression of related cytokines". Medicine. 97 (18): e0620. doi:10.1097/MD.0000000000010620. ISSN 0025-7974. {{cite journal}}: Check date values in: |date= (help)

[19] Long, Hai; Yin, Heng; Wang, Ling; Gershwin, M. Eric; Lu, Qianjin (2016-11-01). "The critical role of epigenetics in systemic lupus erythematosus and autoimmunity". Journal of Autoimmunity. A Comprehensive perspective on systemic lupus erythematosus. 74: 118–138. doi:10.1016/j.jaut.2016.06.020. ISSN 0896-8411.

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 == '''Epigenetics of Autoimmune Disorders''' ==
 [[Autoimmune disease|Autoimmune disorders]] are a diverse class of diseases characterized by a person's immune system attacking their healthy cells. Autoimmune diseases include Lupus, Rheumatoid Arthritis, and Multiple Sclerosis to name a few.<ref name=":3">{{Cite journal|last=Quintero-Ronderos|first=Paula|last2=Montoya-Ortiz|first2=Gladis|date=2012|title=Epigenetics and Autoimmune Diseases|url=http://www.hindawi.com/journals/ad/2012/593720/|journal=Autoimmune Diseases|language=en|volume=2012|pages=1–16|doi=10.1155/2012/593720|issn=2090-0422|pmc=PMC3318200|pmid=22536485}}</ref> Many different factors can account for the onset of autoimmune disorders, however there is a large epigenetic component particularly regarding how alterations in methylation patterns plays a role in these diseases' pathology. Additionally, dysregulation of non-coding RNA and histone modification are key players in exploring the epigenetics underlying these diseases<ref name=":1" /> . Here also discuss evidence comparing prevalence of the diseases compared between dizygotic and monozygotic twins<ref name=":1" /> . Also discuss how/why autoimmune diseasses are more common in women <ref name=":8">{{Cite journal |last=Tomer |first=Yaron |date=2014-01-24 |title=Mechanisms of Autoimmune Thyroid Diseases: From Genetics to Epigenetics |url=https://www.annualreviews.org/doi/10.1146/annurev-pathol-012513-104713 |journal=Annual Review of Pathology: Mechanisms of Disease |language=en |volume=9 |issue=1 |pages=147–156 |doi=10.1146/annurev-pathol-012513-104713 |issn=1553-4006 |pmc=PMC4128637 |pmid=24460189}}</ref> .
-<span style="color: darkred;">'''Hmm. Your last sentence is interesting but counter intuitive to me. Why should X inactivation make it more common? The allele frequency on the X is fixed in the population but females have a "choice" between two X's whereas males have no "choice". In females there is at least the chance that one part of the immune system will use one X and the other part the other X. This sort of thing with respect to blood, musculature, and the nervous system accounts for the reason that hemophilia, muscular dystrophy, and X-linked CNS disorders are more common and problematic in males than in females. So, figure this out. Happy for you to be correct and I want you to explain it very carefully because there might be something new for me to learn.'''
 == Mechanisms of Epigenetic Modifications ==
 Comment: add section describing overview of mechanisms: Use these articles!!! <ref name=":10" /><ref name=":3" /><ref name=":7" /><ref name=":12" />,
+{{font color}}
-{{font color|orange|Continue fleshing out the mechanism of epigenetic medications section. I like how you guys are focusing on the big picture mechanisms, since the mechanism of epigenetic modifications can vary so much between diseases. Just make sure you guys keep the sections, mechanisms of epigenetic modifications and epigenetics of a type of disorder separate and distinct from one another.}}
 === DNA Methylation ===
 Hypomethylation, a loss of DNA methylation, particularly hypomethylation of DNA promoters is heavily associated with multiple different autoimmune disorders, specifically rheumatoid arthritis and systemic lupus erythematosus; Next discuss procainamide and hydralazine induced lupus like condition an d how this relates to hypomethylation as underlying cause of many autoimmune diseases<ref name=":2" />.  Here we would also discuss circRNA and how it is a regulator of methylation and the immune system and how this is tied into many autoimmune conditions<ref name=":4">{{Cite journal |last=Le |first=Michelle |last2=Muntyanu |first2=Anastasiya |last3=Netchiporouk |first3=Elena |date=2020-03 |title=IncRNAs and circRNAs provide insight into discoid lupus pathogenesis and progression |url=http://atm.amegroups.com/article/view/38217/html |journal=Annals of Translational Medicine |volume=8 |issue=6 |pages=260–260 |doi=10.21037/atm.2020.03.56 |pmc=PMC7186711 |pmid=32355704}}</ref> Next write about hypermethylation and its role in autoimmune diseases like Type 1 Diabetes. Include research from the Farh et al paper because this is a big deal in the epigenetic research as far as identifying causal loci via GWAS and iChip analysis<ref name=":2" />.
+{{Color|#800080}}
-{{Color|#800080|I really like how this section is broken down! It goes into good detail about a varying amount of topics. Breaking them up into conditions which lead to epigenetic changes and conditions which are caused by epigenetic changes might be a good way to organize the autoimmune diseases listed.}}
 === Histone Modification ===
@@ Line 44: / Line 42: @@
 === Rheumatoid Arthritis (RA) ===
 [[Rheumatoid arthritis]] is a degenerative autoimmune disease that damages and causes inflammation in a patient’s joint. It is characterized by hypomethylation of synovial cells and CpG island hypomethylation <sup><ref name=":3" /></sup>  . Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, and decreased methylation at the ''Il6'' and ''ERa'' promoter <sup><ref name=":5">{{Cite journal |last=Wu |first=Haijing |last2=Liao |first2=Jieyue |last3=Li |first3=Qianwen |last4=Yang |first4=Ming |last5=Zhao |first5=Ming |last6=Lu |first6=Qianjin |date=2018-11 |title=Epigenetics as biomarkers in autoimmune diseases |url=https://linkinghub.elsevier.com/retrieve/pii/S1521661618301189 |journal=Clinical Immunology |language=en |volume=196 |pages=34–39 |doi=10.1016/j.clim.2018.03.011}}</ref>.</sup>. 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 <ref name=":7">{{Cite journal |last=Ciechomska |first=Marzena |last2=O’Reilly |first2=Steven |date=2016-08-10 |title=Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases |url=https://www.hindawi.com/journals/mi/2016/9607946/ |journal=Mediators of Inflammation |language=en |volume=2016 |pages=e9607946 |doi=10.1155/2016/9607946 |issn=0962-9351 |pmc=PMC4995328 |pmid=27594771}}</ref>. This early stage is more closely observed to be the formation by the TET proteins to cause aberrant global DNA hypomethylation which is the start of the degenerative property and hallmark of Rheumatoid Arthritis <ref name=":7" />. Furthermore, the epigenetic nature of RA is intertwined with the chronic inflammation and significant disability of the immune system in the body that leads to the aberrant histone modifications. The RA development from demethylation of histones in the patient has been observed to express high levels of IL-6 which causes destruction in the joints <ref name=":7" />.
-<span style="color: darkred;">You note a number of genes that show changes. Is there evidence that these are causative or is the change merely assoicated with rheumatoid arthritis. Perhaps, a response to it.
 === Systemic Lupus Erythematosus(SLE) ===
 [[Systemic lupus erythematosus]] is the most common form of lupus and is a condition in which the immune system attacks healthy bodily tissue. Hypomethylation is observed across the epigenome in those with systemic lupus. The promoter regions of many genes including ITGAL, CD40LG, and CD70 are shown to be hypomethylated as well as the 18S and 28S ribosomal gene promoters. In particular, this DNA hypomethylation is thought to alter the chromatin structure of T cells enhancing the immune and inflammatory response observed in those with this condition<ref name=":3" />. Genome wide it has been shown that when comparing the epigenomes of pairs of identical twins in which one twin is afflicted by the condition and one is not, the twin's possessing the condition show global decreases in methylation of their genomes. This hypomethylation causes genes that are traditionally repressed by methylation to be overexpressed particularly in CD4+ T cells. Recently, it has been explored which causative mechanisms are responsible for this genome-wide demethylation and inhibition of DNMT1 has been identified as a potential culprit. DNMT1 is a DNA methyltransferase that conserves methylation patterns from the parent DNA strand to a new copy of DNA during DNA replication. By inhibiting DNMT1 methylation patterns are lost across DNA lines and overall hypomethylation is observed as a result. In particular, it has been observed that DNMT1 expression is lower in immune T-cells. <ref name=":1" />
+{{Color|Green}}
-{{Color|Green|Sienna: Very minor grammar edit, but in the fifth sentence "the twin's possessing the condition" - be sure to take out the apostrophe and "s" if you are talking about one twin. I really like this section that is divided up into different autoimmune diseases - it is easy to read and generally unconfusing. I think there are several grammatical errors/ways to tighten up sentences (for example, inserting commas where you might need a breath while reading, deleting filler words, etc). Strong section though!}}
+{{font color|orange}}
-{{font color|orange|Considering moving the causative mechanisms (DNMT1) for genome-wide demethylation to the previous section about the mechanism epigenetc modifications, and then just referring to it in this section. }}
 === Systemic Sclerosis (SSc) ===
 [[Systemic scleroderma|Systemic sclerosis]] is an autoimmune disease that causes the patient’s skin and connective tissues to tighten and harden due to the uncontrolled accumulation of Extracellular Matrix (ECM) Proteins<sup><ref name=":3" />.</sup>  These ECM Proteins are observed to impact the patient suffering from SSc by affecting the joints and various internal organ systems, even leading to premature death in patients. hypermethylation of CpG islands in Fli1 promoter leads to the overproduction of the fibers affecting the joints and skin thickness of the person suffering from SSC Decreased levels of DNA methyltransferases (DNMTs) in SSc CD4+ T cells suggesting a correlation of this reduced Methylation leading to the progression of SSc and its inflammatory effects, however more research is mentioned to be needed to help further understand this implication<ref name=":5" />.
+{{Color|Green}}
-{{Color|Green|Sienna: Again, really great paragraphs with these individual diseases. I think you summarize the main problem well in the first sentence and effectively lead into the epigenetics of the disease after. I don't know if this is entirely correct, but I think you may not need to spell out the DNMT acronym if you have already defined it previously above. Additionally, the last sentence was a little difficult to read so I would advise revising the syntax. Right now the sentence states that "Decreased levels of DNMT in SSc CD4+ T cells suggesting a correlation..." - however, the reader does not understand what is suggesting a correlation, unless you meant to say that "Decreased levels of DNMTs in SSc CD4+ T cells suggest a correlation...". Just wanted to point out that one sentence in particular!}}
 == Epigenetics of Local Dermatological Autoimmune Disorders ==
@@ Line 95: / Line 91: @@
 <u>COMMENTS</u>
-<span style="color: darkred;">I was quite surprised to find out that there was not a Wikipedia article on this topic. Good job for finding this hole in the encyclopedia. You have a very broad and important topic that touches a great many things. For each one of subtopics you should search Wikipedia to see if a free standing article exists. If it does, you may want to give a mention the disease here with a very short description and then link to the more complete article for more information. Then in your article you would be free to shift your focus to just the relevant epigenetic information.
-<span style="color: darkred;">Thinking about this approach, I am sure that what you are going to find is that some of the articles that you might want to link to are poor quality. In that case you may find yourself editing another article. That is OK. You don't have to pour all of your words into this one document. Parts of your text that describes important aspects of the disease could be carved out and housed elsewhere.
-<span style="color: darkred;">I see that Trevor made a similar comment. Up to you how to handle it.
-<span style="color: darkred;">Is everyone in your group assigned a different subtopic? If so then you should each generate a quick first draft for your section -- even if it means that parts of the draft are still bullet points. After everyone this write a draft of their section trade and be each others' editors and critics. Read each others' drafts/outlines and meet to discuss how to organize the work (this will avoid redundancy such as everyone defining what HDACs are, but other more complex redundancies will also be avoided). Make real organizational suggestions to each other. Tell each other when prose cannot be easily understood. Be thick skinned when you get these comments.
-<span style="color: darkred;">You will be seeing this article in Wikipedia for a very long time to come. You want it to be great. It may evolve but it will still be yours.
-<span style="color: darkred;">Above all keep searching for new information. Sometimes new articles show up (Pubmed) when instead of searching for "Autoimmune Epigenetics" you search for "Autoimmune histone methylation" or some other combination of autoimmune and an enzyme or modification. A very large number of epigenetics papers manage to avoid the use of the word epigenetics. So as you learn terms and the names of enzymes add them to your search criteria.
-<span style="color: darkred;">I think that this article has the potential to be a highly viewed page in Wikipedia. I think that the start here is very good. Now is the time to flesh it out.
-<span style="color:magenta">
-Not much else to add here other than nice job finding this gap in Wikipedia and good work so far gathering sources. I imagine that one of the most difficult things about this article will be in organizing it. Try to break things up into sections where you can (e.g. group SLE and DLE together under a lupus subsection that you can just give one description of what lupus is and then describe the details of each subtype in its own section; or maybe divide them up by systems). Little things like this to save work will be helpful. It's also nicer as a reader to not be confronted by such a large undifferentiated list and can help to more easily see the relationships between diseases. Also, I recommend proofreading each other's sections as you go. Proofing is much easier and more effective when done in small chunks rather than trying to sit down and do many pages worth at once. I make this point because there are quite a few typos throughout this outline (which is fine because this is just an outline), but it will make your lives easier when it comes to finalizing your drafts.
-</span>
-<span style="color:magenta">
-I think Dr. Atkinson mentioned this somewhere, but keep an eye out for causative epigenetic changes (e.g. methylation of the promoter for such-and-such gene causes Hashimoto's) versus epigenetic changes which are merely associated/correlated with a certain disease.
-</span>
+{{Color|green}}
-{{Color|green|First, well done on gathering so much information about this important topic! I think the first thing that stuck out to me is that all of the diseases are listed one after another and may be quite daunting to take in. You already organize them by organ system so that's great! I wonder if you could omit repetitive information or maybe write a small blurb at the beginning of each subsection to allow the reader to take a break occasionally from just reading the disease paragraphs. Just an idea! Although I'm thinking that someone coming to read this article may likely be looking for just one disease (and therefore not read the entire thing). Also, my comments are mainly tailored towards grammar - the biggest thing I wanted to point out first is just to make sure you delete all first-person pronouns by your final draft (we, I, etc.). I can tell that some first-person pronouns are used in the outline for describing what you will write about - but sometimes it gets difficult to distinguish between the outline and actual draft so that's just something to watch out for. Other than that, I would also try reading your sentences out loud to see where you breathe, and put commas/semicolons where needed (in fact, even splitting some sentences into two if they are becoming very long). Overall, a important topic and a great start to your article though! I'm super impressed that this is a newly written article.}}
 == References ==