title: The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan.
abstract: Neutrophils, eosinophils and 'classical' monocytes collectively account for about 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 and minimize the deleterious consequences of prolonged inflammation. 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Kotzin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Spencer
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sam J
authors.initials: SJ
authors.lastname: McCright
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.|Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, Connecticut, 06032, USA.
authors.forename: Dinesh B Uthaya
authors.initials: DBU
authors.lastname: Kumar
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.
authors.forename: Magalie A
authors.initials: MA
authors.lastname: Collet
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Mowel
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.
authors.forename: Ellen N
authors.initials: EN
authors.lastname: Elliott
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.
authors.forename: Asli
authors.initials: A
authors.lastname: Uyar
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Makiya
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Dunagin
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA.
authors.forename: Christian C D
authors.initials: CCD
authors.lastname: Harman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Virtue
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Bailis
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Stein
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hughes
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Arjun
authors.initials: A
authors.lastname: Raj
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.|Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.|Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Loyal A
authors.initials: LA
authors.lastname: Goff
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Klion
authors.affiliation: Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, 06032, USA.|Department of Genetics and Genomic Sciences, University of Connecticut Health Center, Farmington, Connecticut, 06032, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Williams
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.|Howard Hughes Medical Institute, Yale University, New Haven, CT 06510, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.|Division of Transplant Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
mesh_terms: D000483:Alleles; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D017209:Apoptosis; D000072224:Bcl-2-Like Protein 11 / Q000096:biosynthesis / Q000235:genetics*; D002470:Cell Survival; D015536:Down-Regulation; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D000950:Antigens, Ly; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C494192:Ly-6C antigen, mouse; D062085:RNA, Long Noncoding