Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex

Wehrspaun, Claudia C., Haerty, Wilfried ORCID: https://orcid.org/0000-0003-0111-191X and Ponting, Chris P. (2015) Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex. Neurobiology of Aging, 36 (8). 2443.e9-2443.e20. ISSN 0197-4580

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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.

Item Type: Article
Additional Information: Funding Information: The authors would like to thank T. Grant Belgard, Avigail Taylor, and Andreas Heger for helpful comments on analysis and contextualization of results. Claudia C. Wehrspaun was funded by the Wellcome Trust and the NIMH. Wilfried Haerty and Chris P. Ponting were funded by the MRC and ERC (DARCGENs). Publisher Copyright: © 2015 Elsevier Inc.
Uncontrolled Keywords: aging,hematopoiesis,immune system,master regulator,microglia,transcriptional network,neuroscience(all),ageing,clinical neurology,developmental biology,geriatrics and gerontology ,/dk/atira/pure/subjectarea/asjc/2800
Faculty \ School: Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
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Depositing User: LivePure Connector
Date Deposited: 15 Sep 2022 14:30
Last Modified: 18 Apr 2023 20:31
URI: https://ueaeprints.uea.ac.uk/id/eprint/88326
DOI: 10.1016/j.neurobiolaging.2015.04.008

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