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Runx1t1 (Runt-related transcription factor 1; translocated to, 1) epigenetically regulates the proliferation and nitric oxide production of microglia.

Abstract

BACKGROUND

Microglia, the resident immune cells of the brain, undergo rapid proliferation and produce several proinflammatory molecules and nitric oxide (NO) when activated in neuropathological conditions. Runx1t1 (Runt-related transcription factor 1, translocated to 1) has been implicated in recruiting histone deacetylases (HDACs) for transcriptional repression, thereby regulating cell proliferation. In the present study, Runx1t1 expression was shown to localize in amoeboid microglial cells of the postnatal rat brain, being hardly detectable in ramified microglia of the adult brain. Moreover, a marked expression of Runx1t1was induced and translocated to nuclei in activated microglia in vitro and in vivo. In view of these findings, it was hypothesized that Runx1t1 regulates microglial functions during development and in neuropathological conditions.

METHODS AND FINDINGS

siRNA-mediated knockdown of Runx1t1 significantly decreased the expression level of cell cycle-related gene, cyclin-dependent kinase 4 (Cdk4) and proliferation index in activated BV2 microglia. It was also shown that HDAC inhibitor (HDACi) treatment mimics the effects of Runx1t1 knockdown on microglial proliferation, confirming that microglial proliferation is associated with Runx1t1 expression and HDACs activity. Further, Runx1t1 and HDACs were shown to promote neurotoxic effect of microglia by repressing expression of LAT2, L-aminoacid transporter-2 (cationic amino acid transporter, y+ system), which normally inhibits NO production. This was confirmed by chromatin immunoprecipitation (ChIP) assay, which revealed that Runx1t1 binds to the promoter region of LAT2 and this binding increased upon microglial activation. However, the enhanced binding of Runx1t1 to the LAT2 promoter could not repress the LAT2 expression when the BV2 microglia cells were treated with HDACi, indicating that Runx1t1 requires HDACs to transcriptionally repress the expression of LAT2.

CONCLUSION/INTERPRETATION

In conclusion, it is suggested that Runx1t1 controls proliferation and the neurotoxic effect of microglia by epigenetically regulating Cdk4 and LAT2 via its interaction with HDACs.

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  • Authors+Show Affiliations

    ,

    Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    ,

    Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    ,

    Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    ,

    Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore, Singapore.

    Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    Source

    PloS one 9:2 2014 pg e89326

    MeSH

    Analysis of Variance
    Animals
    Blotting, Western
    Brain
    Bromodeoxyuridine
    Cell Proliferation
    Chromatin Immunoprecipitation
    DNA Primers
    Epigenesis, Genetic
    Fluorescent Antibody Technique
    Histone Deacetylases
    Microarray Analysis
    Microglia
    Nitric Oxide
    Proto-Oncogene Proteins
    RNA Interference
    RNA, Small Interfering
    RUNX1 Translocation Partner 1 Protein
    Rats
    Reverse Transcriptase Polymerase Chain Reaction
    Transcription Factors

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24586690

    Citation

    Baby, Nimmi, et al. "Runx1t1 (Runt-related Transcription Factor 1; Translocated To, 1) Epigenetically Regulates the Proliferation and Nitric Oxide Production of Microglia." PloS One, vol. 9, no. 2, 2014, pp. e89326.
    Baby N, Li Y, Ling EA, et al. Runx1t1 (Runt-related transcription factor 1; translocated to, 1) epigenetically regulates the proliferation and nitric oxide production of microglia. PLoS ONE. 2014;9(2):e89326.
    Baby, N., Li, Y., Ling, E. A., Lu, J., & Dheen, S. T. (2014). Runx1t1 (Runt-related transcription factor 1; translocated to, 1) epigenetically regulates the proliferation and nitric oxide production of microglia. PloS One, 9(2), pp. e89326. doi:10.1371/journal.pone.0089326.
    Baby N, et al. Runx1t1 (Runt-related Transcription Factor 1; Translocated To, 1) Epigenetically Regulates the Proliferation and Nitric Oxide Production of Microglia. PLoS ONE. 2014;9(2):e89326. PubMed PMID: 24586690.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Runx1t1 (Runt-related transcription factor 1; translocated to, 1) epigenetically regulates the proliferation and nitric oxide production of microglia. AU - Baby,Nimmi, AU - Li,Yali, AU - Ling,Eng-Ang, AU - Lu,Jia, AU - Dheen,S Thameem, Y1 - 2014/02/19/ PY - 2013/10/07/received PY - 2014/01/17/accepted PY - 2014/3/4/entrez PY - 2014/3/4/pubmed PY - 2014/10/15/medline SP - e89326 EP - e89326 JF - PloS one JO - PLoS ONE VL - 9 IS - 2 N2 - BACKGROUND: Microglia, the resident immune cells of the brain, undergo rapid proliferation and produce several proinflammatory molecules and nitric oxide (NO) when activated in neuropathological conditions. Runx1t1 (Runt-related transcription factor 1, translocated to 1) has been implicated in recruiting histone deacetylases (HDACs) for transcriptional repression, thereby regulating cell proliferation. In the present study, Runx1t1 expression was shown to localize in amoeboid microglial cells of the postnatal rat brain, being hardly detectable in ramified microglia of the adult brain. Moreover, a marked expression of Runx1t1was induced and translocated to nuclei in activated microglia in vitro and in vivo. In view of these findings, it was hypothesized that Runx1t1 regulates microglial functions during development and in neuropathological conditions. METHODS AND FINDINGS: siRNA-mediated knockdown of Runx1t1 significantly decreased the expression level of cell cycle-related gene, cyclin-dependent kinase 4 (Cdk4) and proliferation index in activated BV2 microglia. It was also shown that HDAC inhibitor (HDACi) treatment mimics the effects of Runx1t1 knockdown on microglial proliferation, confirming that microglial proliferation is associated with Runx1t1 expression and HDACs activity. Further, Runx1t1 and HDACs were shown to promote neurotoxic effect of microglia by repressing expression of LAT2, L-aminoacid transporter-2 (cationic amino acid transporter, y+ system), which normally inhibits NO production. This was confirmed by chromatin immunoprecipitation (ChIP) assay, which revealed that Runx1t1 binds to the promoter region of LAT2 and this binding increased upon microglial activation. However, the enhanced binding of Runx1t1 to the LAT2 promoter could not repress the LAT2 expression when the BV2 microglia cells were treated with HDACi, indicating that Runx1t1 requires HDACs to transcriptionally repress the expression of LAT2. CONCLUSION/INTERPRETATION: In conclusion, it is suggested that Runx1t1 controls proliferation and the neurotoxic effect of microglia by epigenetically regulating Cdk4 and LAT2 via its interaction with HDACs. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24586690/Runx1t1__Runt_related_transcription_factor_1 L2 - http://dx.plos.org/10.1371/journal.pone.0089326 DB - PRIME DP - Unbound Medicine ER -