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IRF8 configures enhancer landscape in postnatal microglia and directs microglia specific transcriptional programs
Keita Saeki1, Richard Pan1,2, Eunju Lee1
1Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892.
Abstract:
Microglia are innate immune cells in the brain. Transcription factor IRF8 is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatal Irf8 deletion led to a loss of microglia identity and gain of disease-associated microglia-like genes. Combined analysis of scRNA-seq and scATAC-seq revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Lastly, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with Aβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.
Insights
Transcription factor IRF8 is crucial for microglia development, regulating their gene expression and identity. Deleting IRF8 impairs microglia function and reduces pathology in a mouse model of Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Epigenetics
Background:
- Microglia are the brain's innate immune cells.
- The transcription factor IRF8 is highly expressed in microglia, but its role in postnatal development is unclear.
Purpose of the Study:
- To investigate the role of IRF8 in postnatal microglia development and function.
- To elucidate the epigenetic mechanisms regulated by IRF8 in microglia.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) to identify IRF8 binding sites.
- Single-cell RNA sequencing (scRNA-seq) and single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) to analyze gene expression and chromatin accessibility.
- Analysis of microglia in wild-type and Irf8-deleted mice, including the 5xFAD Alzheimer's disease model.
Main Results:
- IRF8 binds to enhancer regions in a stepwise manner during postnatal microglia development, correlating with increased chromatin accessibility and microglia-specific gene expression.
- Deletion of IRF8 leads to loss of microglia identity, gain of disease-associated microglia genes, and altered DNA methylation patterns.
- In the 5xFAD model, Irf8 deletion reduces microglia interaction with amyloid plaques, decreases plaque size, and lessens neuronal loss.
Conclusions:
- IRF8 establishes the epigenetic landscape essential for postnatal microglia gene expression and identity.
- IRF8 plays a critical role in regulating microglia function and their response to neurodegenerative pathology.
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