Vecellio Matteo, Wu Haijing, Lu Qianjin, Selmi Carlo
Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, IRCCS, via Manzoni 56, 20089 Rozzano, Milan, Italy.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Clin Rheumatol. 2021 Feb;40(2):459-476. doi: 10.1007/s10067-020-05255-5. Epub 2020 Jul 2.
Genomic predisposition cannot explain the onset of complex diseases, as well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodelling and non-coding RNA, are considered to be the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. The paradigmatic cases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SjS) and type-1 diabetes (T1D) share the loss of immunological tolerance to self-antigen influenced by several factors, with a largely incomplete role of individual genomic susceptibility. The most widely investigated epigenetic mechanism is DNA methylation which is associated with gene silencing and is due to the binding of methyl-CpG binding domain (MBD)-containing proteins, such as MECP2, to 5-methylcytosine (5mC). Indeed, a causal relationship occurs between DNA methylation and transcription factors occupancy and recruitment at specific genomic locus. In most cases, the results obtained in different studies are controversial in terms of DNA methylation comparison while fascinating evidence comes from the comparison of the epigenome in clinically discordant monozygotic twins. In this manuscript, we will review the mechanisms of epigenetics and DNA methylation changes in specific immune-mediated rheumatic diseases to highlight remaining unmet needs and to identify possible shared mechanisms beyond different tissue involvements with common therapeutic opportunities. Key Points • DNA methylation has a crucial role in regulating and tuning the immune system. • Evidences suggest that dysregulation of DNA methylation is pivotal in the context of immune-mediated rheumatic diseases. • DNA methylation dysregulation in FOXP3 and interferons-related genes is shared within several autoimmune diseases. • DNA methylation is an attractive marker for diagnosis and therapy.
基因组易感性无法解释复杂疾病的发病机制，同卵双胞胎之间很大程度上不完全一致的情况就很好地说明了这一点。表观遗传机制，包括DNA甲基化、染色质重塑和非编码RNA，被认为是自身免疫性和慢性炎症性疾病中环境刺激与疾病发生之间在允许的遗传背景下的联系。类风湿性关节炎（RA）、系统性红斑狼疮（SLE）、系统性硬化症（SSc）、干燥综合征（SjS）和1型糖尿病（T1D）等典型病例都存在对自身抗原免疫耐受的丧失，这受到多种因素影响，个体基因组易感性的作用在很大程度上并不完全。研究最广泛的表观遗传机制是DNA甲基化，它与基因沉默相关，是由于含甲基-CpG结合域（MBD）的蛋白质，如MECP2，与5-甲基胞嘧啶（5mC）结合所致。实际上，DNA甲基化与特定基因组位点的转录因子占据和募集之间存在因果关系。在大多数情况下，不同研究在DNA甲基化比较方面得到的结果存在争议，而引人入胜的证据来自临床不一致的同卵双胞胎的表观基因组比较。在本手稿中，我们将综述特定免疫介导的风湿性疾病中表观遗传学和DNA甲基化变化的机制，以突出尚未满足的需求，并确定不同组织受累之外可能存在的共同机制以及共同的治疗机会。要点 • DNA甲基化在调节和微调免疫系统中起关键作用。 • 有证据表明DNA甲基化失调在免疫介导的风湿性疾病中至关重要。 • FOXP3和干扰素相关基因中的DNA甲基化失调在几种自身免疫性疾病中都存在。 • DNA甲基化是一种有吸引力的诊断和治疗标志物。
