Abstract
BackgroundMicroglia, 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 FindingssiRNA-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/InterpretationIn 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.
Highlights
Microglia, the resident immune cells of the central nervous system (CNS) transform into an activated state in response to neuropathological conditions, including traumatic brain injury (TBI), causing chronic neurological impairments and neurodegenerative diseases such as the Alzheimer’s disease (AD) [1,2,3,4,5,6,7]
We demonstrated the differential expression pattern of Runx1t1 in the normal and activated microglial cells in vitro as well as in the TBI and AD rat brain models
As microglial cells are known to respond to neuroinflammation and injury, we have examined if there is any change in expression of Runx1t1 in microglia exposed to LPS, which is an endotoxin causing inflammation in the brain
Summary
The resident immune cells of the central nervous system (CNS) transform into an activated state in response to neuropathological conditions, including traumatic brain injury (TBI), causing chronic neurological impairments and neurodegenerative diseases such as the Alzheimer’s disease (AD) [1,2,3,4,5,6,7]. Runx1t1 acts as a transcriptional repressor by recruiting a nuclear corepressor complex containing HDACs [13,17,18,19], which regulate cell cycle progression by upregulating the cell cycle genes Cdk, Cdk through histone deacetylation [20,21]. Runx1t1 (Runt-related transcription factor 1, translocated to 1) has been implicated in recruiting histone deacetylases (HDACs) for transcriptional repression, thereby regulating cell proliferation. 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. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
