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March 16, 2015
Autoimmune Disease Super-Regulators Uncovered
At a Glance
- Scientists discovered key genetic switches, called super-enhancers, involved in regulating the human immune system.
- The finding opens the door to new research into autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.
The immune system has a complex, delicately orchestrated balance. White blood cells called CD4 T cells can mature to become many types of T cells, each of which has a distinct function. Some activate immune responses; others constrain immune responses. When the system is out of balance, uncontrolled reactions can lead to attacks against the body’s own cells and tissues and cause autoimmune disease. Many different tissues can be affected. For example, joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis.
Autoimmune diseases often run in families. However, identifying susceptibility genes has been a challenge. In most cases, a mix of genetic and environmental factors is at play. The genetic variants tied to these diseases tend to lie in regions involved in regulating genes, rather than in genes themselves.
A research team led by Drs. Golnaz Vahedi and John J. O’Shea at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) investigated the role of a recently discovered type of genetic regulatory element called super-enhancers, or stretch-enhancers (SE). Earlier work in other laboratories — including that of NIH Director Dr. Francis S. Collins — showed that SEs are especially powerful switches that control genes important for cell identity. A large number of disease-associated genetic alterations have been found to fall within SEs.
The team searched the genome of T cells for regions bound by a protein called histone acetyltransferase p300, which marks DNA segments that carry SEs. As reported online in Nature on February 16, 2015, the scientists found several hundred genes associated with SEs.
The dominant gene class associated with SEs in T cells encoded cytokines and cytokine receptors. These allow T cells to communicate with other cells and coordinate the immune response. A large fraction of variants previously associated with rheumatoid arthritis and other autoimmune diseases also localized to T cell SEs. However, the greatest SE enrichment in T cells was associated with the gene for BACH2, which has been previously associated with rheumatoid arthritis and other autoimmune diseases. Recently, NIH scientists found that a major function of BACH2 is controlling the activation of T cells.
When the scientists exposed human T cells to tofacitinib — a drug used to treat rheumatoid arthritis — the activities of many genes controlled by SEs were preferentially affected. However, BACH2 levels were unchanged. This result suggests that tofacitinib may act on SEs independent of BACH2 to alter the activities of important T cell genes.
“Three types of data — the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug — are all pointing to the importance of super-enhancers,” Vahedi says. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”
- BACH2 Helps Orchestrate the Immune Response
- Shaking Out Clues to Autoimmune Disease
- The Origins of Autoimmunity-Causing T Cells
- Arthritis Genetics Analysis Aids Drug Discovery
- Autoimmune Diseases
- Immune Cells
References: Super-enhancers delineate disease-associated regulatory nodes in T cells. Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos MR, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ. Nature . 2015 Feb 16. doi: 10.1038/nature14154. [Epub ahead of print]. PMID: 25686607.
Funding: NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Cancer Institute (NCI), and National Human Genome Research Institute (NHGRI); and a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society.