Epigenetic enzyme found to be lacking in some patients with Crohn's disease

March 3, 2017, Massachusetts General Hospital
High magnification micrograph of Crohn's disease. Biopsy of esophagus. H&E stain. Credit: Nephron/Wikipedia

A Massachusetts General Hospital (MGH) research team has found how a variant in an important epigenetic enzyme—previously associated by population-based genetic studies with Crohn's disease and other immune disorders—interferes with the action of the innate immune system, potentially upsetting the healthy balance between the microbial population of the gastrointestinal tract and the immune response. In their paper published in Science Immunology the team reports findings that SP140—an epigenetic reader protein that plays a critical role in determining whether or not target genes are expressed—is essential to suppressing inappropriate gene expression in macrophages, innate immune cells that are critical to maintaining intestinal balance.

"More than 400 enzymes write, read or erase the epigenome, and mutations in these enzymes are some of the most prevalent perturbations in cancers, prompting rigorous efforts to identify compounds that could inhibit their function and reset gene expression," says Kate Jeffrey, PhD of the MGH Gastrointestinal Unit and the Center for the Study of Inflammatory Bowel Disease, corresponding author of the Science Immunology report. "Our knowledge of epigenomic enzyme mutations in immune-mediated disease is lagging well behind the cancer field, and our study—the first to examine the function of SP140 in any detail—shows how its loss in Crohn's disease triggers intestinal inflammation."

SP140 is predominantly expressed in immune cells, and a variant form of the gene has been associated with Crohn's disease, multiple sclerosis and chronic lymphocytic leukemia. Prior to this study both the normal function of the SP140 protein and how the gene variant affected the protein and caused disease were unknown. In a series of experiments, Jeffrey's team showed that the unaltered form of SP140 is required to maintain the appropriate expression of genes that define the identity and function of macrophages. The immune disorder variant—characterized by 17 individual sequence changes - resulted in a loss of SP140 protein that compromised the ability of macrophages to respond to microbial signals.

The researchers also showed that reducing SP140 expression in the immune cells of a mouse model of colitis increased . In addition, examining intestinal biopsy samples from a group of Crohn's disease patients revealed that those in whom SP140 expression was reduced responded better to anti-TNF (tumor necrosis factor) therapy—a treatment for inflammatory conditions that is effective in only about half of Crohn's patients - than did patients with typical SP140 levels.

"Finding this correlation between lower intestinal levels of SP140 and a better response to anti-TNF represents a potential precision medicine strategy for tailoring anti-TNF-like therapies to Crohn's patients carrying the variant form of SP140," says Jeffrey, who is an assistant professor of Medicine at Harvard Medical School. "Our study may also lead to better therapies by highlighting the critical role of epigenetic mechanisms for intestinal health. Although directly targeting SP140 would not be a good option, since its loss is detrimental to intestinal health, leveraging other epigenetic enzyme inhibitors that promote protective innate immune responses in the intestine could be a real therapeutic option"

Additional research is needed to better understand exactly how SP140 normally limits the expression of inappropriate genes and whether this function is limited to macrophages or also occurs in other SP140-expressing , Jeffrey notes. Her team also hopes to investigate the role of the Crohn's-associated SP140 variant in multiple sclerosis and , along with identifying other epigenetic enzymes that may be therapeutically targetable in inflammatory bowel disease and other immune-driven disorders.

Explore further: Crohn's disease risk and prognosis determined by different genes, study finds

More information: "Maintenance of macrophage transcriptional programs and intestinal homeostasis by epigenetic reader SP140," Science Immunology, immunology.sciencemag.org/look … 6/sciimmunol.aag3160

Related Stories

Crohn's disease risk and prognosis determined by different genes, study finds

January 9, 2017
Researchers have identified a series of genetic variants that affect the severity of Crohn's disease, an inflammatory bowel disease - but surprisingly, none of these variants appear to be related to an individual's risk of ...

New insight for developing more effective drugs to combat inflammatory bowel disease

December 21, 2016
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine that includes Crohn's disease and ulcerative colitis. It is commonly treated with one of several available biological drugs that block an ...

Long noncoding RNA found to quell inflammation

July 14, 2016
A long non-coding RNA (lincRNA) - called lincRNA-EPS - responsible for regulating innate immunity has been identified by a team of scientists at the University of Massachusetts Medical School. Abundantly found in macrophages, ...

Recommended for you

Infection site affects how a virus spreads through the body

February 20, 2018
A person is more likely to get infected by HIV through anal intercourse than vaginal, but no one knows quite why. A new study by scientists at the Gladstone Institutes shows that infection sites could affect the immune system's ...

Unexpected immune activation illustrated in the cold

February 19, 2018
Researchers at Utrecht University and Leiden University Medical Center, the Netherlands, have imaged an important immune system on-switch. Their novel technical approach has led to the discovery of two ways in which the immune ...

Immune signature predicts asthma susceptibility

February 16, 2018
Asthma is a chronic inflammatory disease driven by the interplay of genetics, environmental factors and a diverse cast of immune cells. In their latest study, researchers at La Jolla Institute for Allergy and Immunology (LJI) ...

Scientists identify immune cascade that fuels complications, tissue damage in chlamydia infections

February 13, 2018
Closing a critical gap in knowledge, Harvard Medical School scientists have unraveled the immune cascade that fuels tissue damage and disease development in chlamydia infection—the most common sexually transmitted disease ...

Mouse study adds to evidence linking gut bacteria and obesity

February 12, 2018
A new Johns Hopkins study of mice with the rodent equivalent of metabolic syndrome has added to evidence that the intestinal microbiome—a "garden" of bacterial, viral and fungal genes—plays a substantial role in the development ...

Cancer killing clue could lead to safer and more powerful immunotherapies

February 12, 2018
New research could help to safely adapt a new immunotherapy—currently only effective in blood cancers—for the treatment of solid cancers, such as notoriously hard-to-treat brain tumours.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.