Autoimmune Disease Super-Regulators Uncovered

NIH | MARCH 20, 2015

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.

Scanning electron micrograph of a human T cell. Source: National Institute of Allergy and Infectious Diseases (NIAID)

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). 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.

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. 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.

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.

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