Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


NIH researchers reveal link between powerful gene regulatory elements and autoimmune diseases


Findings point to potential drug targets

Investigators with the National Institutes of Health have discovered the genomic switches of a blood cell key to regulating the human immune system. The findings, published in Nature today, open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.

This is a scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor.

Credit: National Institute of Allergy and Infectious Diseases (NIAID)

The senior author of the paper, John J. O'Shea, M.D., is the scientific director at NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases. The lead author, Golnaz Vahedi, Ph.D., is a postdoctoral fellow in Dr. O'Shea's lab in the Molecular Immunology and Inflammation Branch. The study was performed in collaboration with investigators led by NIH Director, Francis S. Collins, M.D., Ph.D., in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute.

Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases, for example, the joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families.

"We now know more about the genetics of autoimmune diseases," said NIAMS Director Stephen I. Katz, M.D., Ph.D. "Knowledge of the genetic risk factors helps us assess a person's susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual."

Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.

Dr. O'Shea's team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of Dr. Collins and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction.

Dr. O'Shea's team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease.

"Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach," said Dr. O'Shea. "From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets--their key proteins--and thereby where we are most likely to find genetic alterations that confer disease susceptibility."

Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

But the researchers' most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs. Additional experiments provided further evidence for a central role for SEs in rheumatoid arthritis. When the scientists exposed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs 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," said Dr. Vahedi. "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."


Additional lead investigators included NIAMS Deputy Scientific Director Vittorio Sartorelli, M.D., Nicholas P. Restifo, M.D., at the NIH's National Cancer Institute, and Yijun Ruan, Ph.D., at The Jackson Laboratory in Farmington, Connecticut.

This work was supported by the NIAMS intramural program under project number ZIA AR041159-07 and by NCI grant R01 CA186714.

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SC, Erdos M, Davis SR, Roychoudhuri R, Restifo NP, Gadina M, Tang Z, Ruan Y, Collins FS, Sartorelli V, O'Shea JJ. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature. Online February 16, 2015. DOI: 10.1038/nature14154.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Media Contact

Trish Reynolds

Trish Reynolds | EurekAlert!

More articles from Life Sciences:

nachricht North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich

nachricht Researchers Discover New Anti-Cancer Protein
22.03.2018 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers Discover New Anti-Cancer Protein

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

Modular safety concept increases flexibility in plant conversion

22.03.2018 | Trade Fair News

New interactive map shows climate change everywhere in world

22.03.2018 | Earth Sciences

New technologies and computing power to help strengthen population data

22.03.2018 | Earth Sciences

Science & Research
Overview of more VideoLinks >>>