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Long noncoding RNA found to quell inflammation

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WORCESTER, MA – 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, lincRNA-EPS keeps the genes that trigger inflammation turned off until a pathogen is encountered. This discovery points to an unrecognized role for lincRNAs in the immune system and may lead to new insights into inflammatory diseases caused by uncontrolled immune responses such as lupus or inflammatory bowel disease.

"These findings suggest that there is an unexplored layer of regulation controlling inflammatory and immune responses," said Katherine A Fitzgerald, PhD, professor medicine and senior author of the study, which was published in Cell. "We've demonstrated an important functional role of a lincRNA in the immune system."

Long non-coding RNAs are non-protein coding transcripts arbitrarily defined as longer than 200 nucleotides (to help distinguish them from microRNA, short interfering RNAs, Piwi-interacting RNAs and other short RNAs). It is believed that lincRNA may account for the majority of RNA transcription in the human genome. "Despite their abundance, little is known about the functions of these long RNAs play in the immune system," said Fitzgerald. "In trying to understand the complex genetic circuitry that controls the immune system, immunologists have historically focused on the 2 percent of the genome that code for proteins."

Using a mouse model lacking lincRNA-EPS, Fitzgerald and colleagues showed that in their normal state, macrophages (a type of white blood cell that defends against infections) produce lincRNA-EPS to prevent the spontaneous activation of immune response genes. However, when macrophages detect a potential pathogen, lincRNA-EPS expression is suppressed to release this brake, and the pro-inflammatory response is initiated. Mice that were lacking lincRNA-EPS exhibited increased levels of cytokines and inflammatory responses that led to toxic shock.

Researchers found that lincRNA-EPS keeps the expression of immune genes in check by controlling the position of the nucleosome so they are inaccessible. When lincRNA-EPS is no longer expressed in the cells, the structure of the genome changes so critical immune-related genes are exposed for transcription. When researchers reintroduced lincRNA-EPS into the cell, expression of immune genes returned to normal levels.

"We have also found that the expression of lincRNA-EPS itself is very carefully regulated and is very sensitive to slight changes," said Maninjay K. Atianand, PhD, a postdoctoral fellow at UMMS and first author of the study. "This lincRNA is an important component in the molecular circuitry to prevent spontaneous activation of key immune genes. These findings have important implications for the potential role that lincRNAs may play in chronic inflammation and immune pathologies."

The next step for Fitzgerald and colleagues is to determine what role lincRNA-EPS plays in intestinal inflammation and its function in colon, where it is abundantly found.

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About the University of Massachusetts Medical School

The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, is comprised of the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the Commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. The Medical School attracts more than $266 million annually in research funding, placing it among the top 50 medical schools in the nation. In 2006, UMMS's Craig C. Mello, PhD, Howard Hughes Medical Institute Investigator and the Blais University Chair in Molecular Medicine, was awarded the Nobel Prize in Physiology or Medicine, along with colleague Andrew Z. Fire, PhD, of Stanford University, for their discoveries related to RNA interference (RNAi). The 2013 opening of the Albert Sherman Center ushered in a new era of biomedical research and education on campus. Designed to maximize collaboration across fields, the Sherman Center is home to scientists pursuing novel research in emerging scientific fields with the goal of translating new discoveries into innovative therapies for human diseases.

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