Loss of Epigenetic Enzyme In Crohn's Disease Triggers Intestinal Inflammation

Study is the first to examine the function of SP140 protein in inflammatory diseases.

The protein SP140 plays a critical role in innate immune function and intestinal health, a recent study found.

A variant form of SP140—–predominately expressed in immune cells––has been associated with Crohn’s disease, multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). Previously, it was unclear how both the normal function of SP140 and the gene variant affected the protein and caused disease.

In a study published in Science Immunology, investigators showed that the unaltered form of SP140 is required to maintain the expression of genes that define macrophage identity and function.

The immune disorder variant is characterized by 17 individual sequence of changes, and resulted in the loss of SP140 that compromised the ability of macrophages to respond to microbial signals.

“More than 400 enzymes write, read or erase the epigenome, and mutations in these enzymes are some of the most prevalent perturbations in cancers, promoting rigorous efforts to identify compounds that could inhibit their function and reset gene expression,” said corresponding author Kate Jeffrey, PhD. “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.”

In a mouse model of colitis, the reduction of SP140 expression in the immune cells increased intestinal inflammation. The investigators also examined intestinal biopsy samples obtained from patients with Crohn’s disease, and found that those with a reduction in SP140 expression responded better to anti-tumor necrosis factor therapy (anti-TNF) compared with patients who had typical SP140 levels.

“Findings the 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,” Jeffrey said. “Our study may also lead to better inflammatory bowel disease 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.”

Although the study’s findings provide insight, the authors noted that more research needs to be done to better understand precisely how SP140 normally limits the expression of inappropriate genes and whether this function is limited to macrophages, or if it also occurs in other SP140-expressing immune cells.

The investigators hope to examine the role of the Crohn’s-associated SP140 variant in MS and CLL, and identify other epigenetic enzymes that could serve as therapeutic targets in inflammatory bowel disease.