Epigenetics Meets Rheumatology
Nan Shen, MD, PhD, director of Shanghai Institute of Rheumatology, took the stage to speak about non-coding genes that account for most of the transcription of the genome. He described these non-coding sequences as quite complex and walked the audience through a (relatively) simple description. He explained the long non-coding RNAs (lncRNAs) in the nucleus and cytoplasm have multiple functions, including epigenetic modification, transcriptional regulation, post-transcriptional regulation and post-translational regulation. They thus regulate gene expression at multiple levels by interacting with DNA, RNA and protein. Perhaps of most interest to rheumatologists, Dr. Shen stated, they are also critical for immune cell development, activation and function. They are likely to be especially important in rheumatology because several lncRNAs are dysregulated in rheumatic diseases.
Dr. Shen and others have focused their efforts on identifying the lncRNAs relevant to systemic lupus erythematosus (SLE). They have used several strategies, including data mining, to identify the lncRNAs involved in immune system regulation, those associated with disease activity, those differentially expressed between patients with lupus and healthy controls, and those located near genetic susceptibility loci. Their efforts have yielded an lncRNA stimulated by interferon that appears to be important in the pathophysiology of SLE.
Epigenetics & Psoriasis
Qianjin Lu, MD, director of the Institute of Dermatology at Central South University, Changsha, Hunan, China, discussed the role of epigenetics in a mouse model of psoriasis. He noted the literature has documented monozygotic twins who are discordant for psoriasis.
Psoriasis is associated with inflammatory cell infiltration, increased cytokine production and hyperproliferation of keratinocytes. Both genetic and environmental factors create the epigenetic profile of psoriasis, demonstrating that DNA methylation changes gene expression. Moreover, skin biopsies of patients with psoriasis reveal higher global DNA methylation, and researchers have now been able to use epigenome-wide association analysis to identify nine skin DNA methylation loci for psoriasis. In addition, high throughput data analysis has identified methylated genes from different clinical specimens of psoriasis patients. More detailed studies have revealed the DNA in skin lesions and peripheral blood mononuclear cells (PBMCs) of patients with psoriasis are hypermethylated and include abnormal histone modifications.
Non-coding microRNA (miRNA) also plays a role in the modulation of immunological mechanism of psoriasis. Dr. Lu’s group has found several key miRNAs, such as miRNA-210, are specifically overexpressed in psoriasis, whereas other known miRNAs are specifically downregulated in psoriasis. A closer examination of immune cells revealed miRNA-210 expression is elevated in CD4+ T cells, as well as in skin lesions from patients with psoriasis. Moreover, expression levels of miRNA-210 correlate with disease severity. The research by Dr. Lu and colleagues suggests miRNA-210 contributes to the altered balance between pathogenic Th1/Th17 cells and Th2 cells in patients with psoriasis and accelerates the development of disease. Their results thus detail a crucial role for miRNA-210 in the immune imbalance of T lymphocyte subsets in psoriasis and suggest a potential therapeutic approach.