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Morrbid gene fights infection havoc

A new study has identified the Morrbid gene is expressed to regulate immune cell lifespan via long non-coding RNAs (lncRNAs). If lncRNAs are key to fighting infection and preventing inflammatory disorders, new drug targets are possible for inflammatory disorders.

The gene for a lncRNA called Morrbid was identified in 2013 by Henao-Mejia when a postdoctoral fellow in the lab of Richard Flavell, PhD, FRS, at Yale University, the study's coauthor, in collaboration with another coauthor, Adam Williams, The Jackson Laboratory for Genomic Medicine, Bar Harbor, Maine.

After Henao-Mejia established his lab at Penn in 2014, he and his students led the team that eventually identified the immune cells in which Morrbid is expressed and illuminated its role in regulating immune cell lifespan. The study appears as an advance online publication in Nature this month.

According to research led by Jorge Henao-Mejia, MD, PhD, Assistant Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania, the discovery offers a potential drug target for several inflammatory disorders. These disorders are distinguished by organ damage from the abnormal lifespan of white blood cells.

Long non-coding RNAs are often abundant
in cells, yet they don't code for proteins.

The human genome contains about 20,000 protein-coding genes – less than 2 percent of the total genome. But, 70 percent of the human genome actively produces about 10,000 lncRNAs — and the function of the majority of them is unknown.

Morrbid controls the life span of circulating myeloid cells, key to maintaining a proper balance between fighting infection and inflammation.

The gene for Morrbid is conserved across species, including mice and humans, and is specific to these immune cells: neutrophils, eosinophils, and monocytes.

However, these cell types make up 70 percent of all circulating white blood cells and induce very potent in reactions. Sometimes, reactions so strong they cause damage to surrounding healthy tissue. This reactive system is akin to human first responders appearing at a crisis to lend immediate aid. But, how does the body keep this initial over-zealous-guard-dog response in check? How does the body know when and how to tell the cells to back off?

"These cells are extremely short-lived — less than one day — and their life span is tightly regulated to meet the demands of the organism.

"When we finally understand the molecular mechanisms by which their life span is tightly regulated, perhaps we will be able correct for when it goes awry, or power it up as needed."

Henao-Mejia PhD, Division of Transplant Immunology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Morrbid regulates cell lifespan by controlling the expression of Bim, a nearby gene that in turn controls programmed cell death in response to the amount of cytokines and metabolites in the environment surrounding cells. Morrbid essentially overrides signaling that prevents immune cells' premature death.

By deleting Morrbid in mice, the team saw a drastic reduction in immune cells that normally express Morrbid. Therefore, mice had less ability to fight infection — but did gain protection against inflammation.

The expression of the human version of the gene, MORRBID, is impaired in patients with Hypereosinophilic Syndrome (HES). In that sydrome, the lifespan of certain immune cells is not kept in check, resulting in organ damage from continuous inflammation. Yet, in one reported case of a woman with a seven year history of HES, her pregnancy resulted in the delivery of a healthy infant without complications, and no evidence of elevated eosinophils in the infants blood. During pregnancy the patient experienced significant reduction of eosinophils in her blood and resolution of signs and symptoms related to hypereosinophilia.

"Knowing this, Morrbid might be a good drug target for this uncommon disease and maybe even have a potential role for chronic diseases like asthma, inflammatory bowel disease, obesity, or cancer — all of which have an errant inflammatory component.

"In the near future, we would like to concentrate our efforts to develop strategies to modulate the function of MORRBID in human cells as an effective therapeutic tool against inflammatory disease."

Henao-Mejia PhD

Neutrophils, eosinophils and ‘classical’ monocytes collectively account for ~70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and ‘classical’ monocytes in response to pro-survival cytokines. To control the lifespan of these cells, Morrbid regulates the transcription of its neighboring pro-apoptotic gene, Bcl2l11 (Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows for rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in patients with hypereosinophilic syndrome, this lncRNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.

Search terms: Gene regulation in immune cells Immune cell death

This work was funded by the National Institutes of Health (R21AI110776-01 T32-DK00778017, F30-DK094708, T32-AI05542803, 1DP2OD008514, 1R33EB019767), The Institute for Immunology at Penn, the Howard Hughes Medical Institute, and The Children's Hospital of Philadelphia.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
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lncRNAs involved in the control of organ differentiation and development
Image Credit: Jan-Wilhelm Kornfeld, Max-Planck Institute for Metabolism Research



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