Kotzin et al. explored the molecular mechanism controlling the shortest-lived cells of the immune system—neutrophils, eosinophils, and monocytes—all of which are myeloid cells of the innate immune system. The long noncoding RNA Gm14005, which the authors renamed Morrbid for “myeloid RNA regulator of Bim-induced death,” was identified as an RNA preferentially expressed in mature short-lived myeloid cells, and mice lacking Morrbid had reduced numbers of eosinophils, neutrophils, and Ly6Chi monocytes in circulation and tissues. The Morrbid knockout mice also exhibited increased susceptibility to bacterial infection and reduced eosinophil-driven allergic lung inflammation. Progenitors of these myeloid cells were not affected by Morrbid knockout, and wild-type progenitors have low expression of Morrbid, which subsequently increases to a maximum in the mature cells. Ex vivo Morrbid knockout short-lived myeloid cells underwent rapid apoptosis, and cell labeling with BrdU revealed a decrease in the life span of these cells. Morrbid is close to the proapoptotic gene Bcl2l11, which encodes BIM. Morrbid knockout eosinophils, neutrophils, and LysChi monocytes had increased abundance of BIM mRNA and protein. Cytokine deprivation of cultured bone marrow–derived eosinophils reduced Morrbid expression and increased Bcl2l11 expression, and addition of any of the cytokines of the common β-chain receptor family [interleukin-3 (IL-3), IL-5, or granulocyte-macrophage colony-stimulating factor (GM-CSF) induced Morrbid expression and reduced Bcl2l11 expression. Various chromatin, crosslinking, and allele-specific combination knockout experiments revealed that Morrbid bound and functioned in cis to the Bcl2l11 promoter. Morrbid-mediated repression involved the recruitment of the polycomb repressive complex 2 (PRC2) to the Bcl2l11 promoter through a direct interaction between Morrbid and the PRC2 component EZH2. Deletion of Bcl2l11 in cis, but not in trans, of the Morrbid allele rescued short-lived myeloid cell numbers in mice. Morrbid is conserved in humans, and overexpression of MORRBID occurred in patients with hypereosinophilic syndrome that was associated with increased IL-5. Thus, expression of a long noncoding RNA serves as a locus-specific timer controlling the life span of short-lived myeloid cells.
J. J. Kotzin, S. P. Spencer, S. J. McCright, D. B. U. Kumar, M. A. Collet, W. K. Mowel, E. N. Elliott, A. Uyar, M. A. Makiya, M. C. Dunagin, C. C. D. Harman, A. T. Virtue, S. Zhu, W. Bailis, J. Stein, C. Hughes, A. Raj, E. J. Wherry, L. A. Goff, A. D. Klion, J. L. Rinn, A. Williams, R. A. Flavell, J. Henao-Mejia, The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell life span. Nature 537, 239–243 (2016). [PubMed]