Alterations in DNA methylation play important roles not only in cellular differentiation, but also in disease.
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Explore This IssueMarch 2019
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SDTFs and LDTFs thus bind to enhancers distributed asymmetrically throughout the genome. Genomic regions of dense deposition are referred to as super-enhancers, and these super-enhancers are linked to cell identity. For example, in many cases, the loci identified via genome-wide association studies hits are enriched for super-enhancer architecture, and Dr. O’Shea showed data indicating super-enhancers reflect both cell identity and cell state.
Rheumatologists should be aware of these super-enhancers because “the drugs that we are giving patients are more likely to affect super-enhancer regions,” noted Dr. O’Shea. “Deciphering all these switches in immune cells is an enormous challenge, but in the future, better knowledge of these numerous regulatory elements should create tremendous opportunities for new treatments.” For example, Dr. O’Shea and colleagues have found drugs like tofacitinib preferentially affect rheumatoid arthritis (RA) risk genes with super-enhancer structure, as opposed to those with typical enhancer architecture.
Esteban Ballestar, PhD, senior group leader of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute, Barcelona, expanded the conversation to B cells and antibodies. In particular, he described the DNA methyltransferase family of enzymes, which include ten-eleven translocation (TET) enzymes that actively demethylate DNA. Dr. Ballestar reiterated DNA methylation is linked to gene expression, and he specifically discussed common variable immunodeficiency, which is the most frequent symptomatic primary antibody deficiency. It has an incidence of 1 in 25,000 and is caused by a severe deficiency of switched memory B cells and a marked decrease in IgG. Closer examination has revealed “these patients not only have a smaller number of these memory cells, but they have a defect in demethylating these genes,” explained Dr. Ballestar.
Role of Aging in Autoimmunity
Raymond Yung, MD, director of the Geriatrics Center and Institute of Gerontology at the University of Michigan, Ann Arbor, spoke about the role of aging in autoimmunity. Dr. Yung is also the Jeffrey B. Halter Professor of Geriatric Medicine, chief of the Division of Geriatric and Palliative Medicine, director of the University of Michigan Institute of Gerontology and Geriatrics Center at Michigan Medicine. Although aging is associated with an increased prevalence of serological autoimmunity, the increase, surprisingly, does not necessarily translate into a high incidence of full-blown autoimmune disease in old age. Dr. Yung examined the paradox and found evidence that suggested epigenetics is an important process that influences aging and may serve as the link between aging and chronic diseases.
Dr. Yung used the term inflamm-aging to describe how, as humans age, blood and serum have increased levels of interleukin 6 (IL-6), IL-8, tumor necrosis factor (TNF) and C-reactive protein. Although it is not yet obvious why these cytokines increase as people age, Dr. Yung put forth the hypothesis the body encounters numerous infectious agents and develops multiple chronic infections as it ages, and these infections stimulate the immune system. “Over time, the body reacts by not returning to baseline,” suggested Dr. Yung. He noted other factors beyond infection could also be driving this phenomenon, including obesity, microbiota, renin-angiotensin, hormonal changes, redox stress, telomere dysfunction and glycation.
Inflamm-aging extends beyond a shift in naive and memory subsets to include an enlargement of fat-associated lymphoid clusters, as well as an increase in adipose tissue macrophages. Dr. Yung concluded, “The immune system is complicated. Aging is complicated. When you put the two of them together, it gets really complicated.”