Integrated Multi-omics Reveals MEF2C as a Direct Regulator of Microglial Immune and Synaptic Programs

Background: Patients with MEF2C haploinsufficiency exhibit a clinically recognizable syndrome characterized by intellectual disability, intractable seizures, and autism spectrum behaviors. Although MEF2C is well-established as a critical transcription factor in cardiac development and neuronal function, its regulatory roles in microglia—the brain’s resident immune cells—remain largely uncharacterized. This gap is particularly striking given that MEF2C syndrome manifests predominantly with neurological symptoms while cardiac defects are rare. Results: Using isogenic human iPSC-derived microglia with MEF2C knockout, we conducted integrated ChIP-seq and RNA-seq analyses. MEF2C directly binds 1,258 genomic sites and regulates 755 genes (FDR < 0.05). Integration of these datasets identified 69 high-confidence direct targets with significant overlap (p = 8.87 × 10⁻⁵). Among the most strongly affected genes were ADAMDEC1, a microglia-enriched metalloprotease essential for extracellular matrix remodeling (log₂FoldChange = -4.76, adjusted p = 3.30 × 10⁻¹⁹), and CARD11, a key component of NF-κB signaling (log₂FoldChange = -5.16, adjusted p = 5.95 × 10⁻⁵). Pathway analysis revealed profound disruption of core microglial functions, most notably Fcγ receptor signaling (p = 3.11 × 10⁻⁷), which is critical for antibody-mediated phagocytosis and synaptic pruning. Additional enrichments were observed in immune response pathways and synaptic organization processes, indicating that MEF2C loss impairs microglia-mediated refinement of neural circuits. Conclusion: These results position MEF2C as a master regulator orchestrating both immune and synaptic transcriptional programs in microglia. The observed dysregulation—particularly in Fcγ receptor signaling—provides a mechanistic link to the neurological phenotype of MEF2C syndrome. Experimental validation in wet-lab systems will be required to confirm these regulatory relationships and their functional consequences.