IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs
Keita Saeki1, Richard Pan2,3, Eunju Lee2
1Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. saekik2@nih.gov.
Abstract:
Microglia are innate immune cells in the brain. Transcription factor IRF8 (interferon regulatory factor 8) 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 (DAM)-like genes. Combined analysis of single-cell (sc)RNA sequencing and single-cell transposase-accessible chromatin with sequencing (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. Last, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.
Insights
Interferon regulatory factor 8 (IRF8) is crucial for microglia development and identity. Deleting IRF8 causes loss of microglia traits and exacerbates Alzheimer's disease pathology in mice.
Area of Science:
- Neuroscience
- Immunology
- Epigenetics
Background:
- Microglia are the brain's innate immune cells.
- 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 understand how IRF8 influences the epigenetic landscape and gene expression in microglia.
Main Methods:
- Chromatin immunoprecipitation sequencing (ChIP-seq) to identify IRF8 binding sites.
- Single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) for multi-omic analysis.
- Genetic deletion of IRF8 in mouse models, including the 5xFAD Alzheimer's disease model.
Main Results:
- IRF8 binds to enhancers in developing microglia, correlating with increased chromatin accessibility and microglia-specific gene expression.
- Loss of IRF8 leads to a loss of microglial identity and a gain of disease-associated microglia (DAM) signatures.
- IRF8 is essential for establishing microglia-specific DNA methylation patterns.
- IRF8 deletion in 5xFAD mice reduces amyloid-beta plaque interaction, plaque size, and neuronal loss.
Conclusions:
- IRF8 plays a critical role in establishing the epigenetic landscape necessary for postnatal microglia gene expression and identity.
- IRF8 is a key regulator of microglial maturation and function, impacting neuroinflammation and neuroprotection in Alzheimer's disease models.
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