The long non-coding RNAMorrbidregulatesBimand short-lived myeloid cell lifespan

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Neutrophils, eosinophils and ‘classical’ monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body1,2. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation1,2. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termedMorrbid, 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,Morrbidregulates the transcription of the neighbouring pro-apoptotic gene,Bcl2l11(also known asBim), by promoting the enrichment of the PRC2 complex at theBcl2l11promoter to maintain this gene in a poised state. Notably,Morrbidregulates this process incis, enabling allele-specific control ofBcl2l11transcription. Thus, in these highly inflammatory cells, changes inMorrbidlevels provide a locus-specific regulatory mechanism that allows rapid control of apoptosis in response to extracellular pro-survival signals. AsMORRBIDis 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.

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