Gene transcription can be as capricious as the Fates, who personified destiny and reserved the right to cut the thread of life, but it might yet be persuaded to be as balanced as Justice, a sister to the Fates who was dedicated to keeping the order and setting limits to any action. Depending on how gene transcription metes out the supply of Morrbid, a long noncoding RNA (lncRNA), certain immune cells may have longer or shorter lifespans, determining whether immune responses go too far, or whether a proper balance is maintained between fighting infection and inflammation.

The gene for a lncRNA called Morrbid was identified in 2013 by Jorge Henao-Mejia, M.D., Ph.D., who is currently an assistant professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. Subsequent work by Dr. Henao-Mejia and colleagues has identified the immune cells in which Morrbid is expressed. This work has also illuminated the mechanism by which Morrbid regulates immune cell lifespan.

This new work appeared August 15 in the journal Nature, in an article entitled, “The Long Non-coding RNA Morrbid Regulates Bim and Short-lived Myeloid Cell Lifespan.” The article clarifies how immune cells called myeloid cells—neutrophils, eosinophils, and “classical” monocytes—are regulated. According to the article’s authors, precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses while minimizing the deleterious consequences of prolonged inflammation.

“These cells are extremely short-lived—less than 1 day—and their life span is tightly regulated to meet the demands of an organism,” said Dr. Henao-Mejia. “If we understand the molecular mechanisms by which their life span is tightly regulated, perhaps we could correct it when the control goes awry or power it up, when needed.”

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

“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,” wrote the authors of the Nature article. “Notably, Morrbid regulates this process in cis, enabling allele-specific control of Bcl2l11 transcription.”

Essentially, in the highly inflammatory myeloid cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows for rapid control of apoptosis in response to extracellular prosurvival signals.

By deleting Morrbid in mice, Dr. Henao-Mejia and colleagues instigated a drastic reduction in the frequency of immune cells that normally express Morrbid. Therefore, the mice had less ability to fight infection but gained protection against inflammation.

The expression of the human version of the gene, MORRBID, is impaired in patients with hypereosinophilic syndrome, in which the lifespan of some immune cells is not kept in check, causing inflammation and organ damage. “Knowing this, Morrbid might be a good drug target for this uncommon disease and maybe even has a potential role for chronic diseases like asthma, inflammatory bowel disease, obesity, or cancer, all of which have an errant inflammatory component to their symptoms,” noted Dr. Henao-Mejia. “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.”

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