title: Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.
abstract: Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Cronk
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Noël C
authors.initials: NC
authors.lastname: Derecki
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Ji
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Lampano
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Smirnov
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Baker
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Norris
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Ioana
authors.initials: I
authors.lastname: Marin
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Coddington
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot Israel 76100.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Wolf
authors.affiliation: Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: Cardiovascular Research Center, Cardiovascular Division, Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Tajie H
authors.initials: TH
authors.lastname: Harris
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot Israel 76100.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA. Electronic address: vladimir.litvak@umassmed.edu.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.affiliation: Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Graduate Program in Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: kipnis@virginia.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D018899:CpG Islands / Q000276:immunology*; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000276:immunology; D008136:Longevity / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D015518:Rett Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; C045073:Cre recombinase; D019426:Integrases