title: Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex.
abstract: Microglia form the immune system of the brain. Previous studies in cell cultures and animal models suggest altered activation states and cellular senescence in the aged brain. Instead, we analyzed 3 transcriptome data sets from the postmortem frontal cortex of 381 control individuals to show that microglia gene markers assemble into a transcriptional module in a gene coexpression network. These markers predominantly represented M1 and M1/M2b activation phenotypes. Expression of genes in this module generally declines over the adult life span. This decrease was more pronounced in microglia surface receptors for microglia and/or neuron crosstalk than in markers for activation state phenotypes. In addition to these receptors for exogenous signals, microglia are controlled by brain-expressed regulatory factors. We identified a subnetwork of transcription factors, including RUNX1, IRF8, PU.1, and TAL1, which are master regulators (MRs) for the age-dependent microglia module. The causal contributions of these MRs on the microglia module were verified using publicly available ChIP-Seq data. Interactions of these key MRs were preserved in a protein-protein interaction network. Importantly, these MRs appear to be essential for regulating microglia homeostasis in the adult human frontal cortex in addition to their crucial roles in hematopoiesis and myeloid cell-fate decisions during embryogenesis.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Section on Neuropathology, Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, IRP, NIMH, NIH, Bethesda, MD, USA. Electronic address: claudia.wehrspaun@dpag.ox.ac.uk.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Wehrspaun
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Physiology, Anatomy and Genetics, MRC Functional Genomics Unit, University of Oxford, UK.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Haerty
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Department of Physiology, Anatomy and Genetics, MRC Functional Genomics Unit, University of Oxford, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
mesh_terms: D000375:Aging; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology; D066264:Datasets as Topic; D005625:Frontal Lobe; D006410:Hematopoiesis / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000502:physiology; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D060066:Protein Interaction Maps; D011518:Proto-Oncogene Proteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D059467:Transcriptome / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; C493728:RUNX1 protein, human; C067143:TAL1 protein, human
keywords: Aging; Hematopoiesis; Immune system; Master regulator; Microglia; Transcriptional network