The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan

The long non-coding RNA Morrbid controls myeloid cell lifespan and regulates apoptosis by repressing the adjacent pro-apoptotic Bcl2l11 gene in cis . Keeping myeloid cells on a tight leash Neutrophils, eosinophils and 'classical' monocytes are a first line of defense against pathogens, but their actions can also cause inflammatory diseases. It is important that the lifespan of these myeloid cells is regulated in order to minimize deleterious effects. Jorge Henao-Mejia and colleagues show here that a long non-coding RNA termed Morrbid specifically controls the lifespan of short-lived myeloid cells by regulating expression of the pro-apoptotic Bcl2l11 ( Bim ) gene. MORRBID is present in humans and is highly upregulated in human hypereosinophilic diseases, so its inhibition may represent a novel therapeutic approach in pathologies influenced by altered myeloid lifespan. Neutrophils, eosinophils and ‘classical’ monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body 1 , 2 . Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation 1 , 2 . However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid , which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice. To control the lifespan of these cells, Morrbid regulates the transcription of the neighbouring pro-apoptotic gene, Bcl2l11 (also known as 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 rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in individuals with hypereosinophilic syndrome, this long non-coding RNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.