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

TL;DR

This study reveals that MEF2C directly regulates genes involved in immune responses and synaptic functions in microglia, providing insights into its role in neurodevelopmental disorders.

Contribution

It identifies MEF2C as a key transcriptional regulator of microglial immune and synaptic programs through integrated genomic analyses.

Findings

MEF2C binds to 1,258 genomic loci in microglia.

Regulation of 755 genes by MEF2C, including key immune and synaptic genes.

Disruption of Fc-gamma receptor signaling and synaptic pathways.

Abstract

Background: Patients carrying MEF2C haploinsufficiency develop a recognizable neurodevelopmental syndrome featuring intellectual disability, treatment-resistant seizures, and autism spectrum behaviors. While MEF2C's critical roles in cardiac development and neuronal function are well-established, its specific transcriptional operations within microglia (the brain's resident immune cells) have remained surprisingly undefined. This knowledge gap is particularly notable given that MEF2C syndrome patients consistently present with neurological symptoms while cardiac abnormalities are rarely observed. Results: We used human iPSC-derived microglia with MEF2C knockout to perform integrated ChIP-seq and RNA-seq analyses. Our data demonstrate that MEF2C directly binds 1,258 genomic loci and regulates 755 differentially expressed genes (FDR < 0.05). Integration identified 69 high-confidence direct targets with statistically significant overlap (p = 8.87 x 10^-5). The most dramatic changes included ADAMDEC1, a microglia-enriched metalloprotease for extracellular matrix remodeling (log2FC = -4.76, adj. p = 3.30 x 10^-19), and CARD11, an NF-kappaB signaling component (log2FC = -5.16, adj. p = 5.95 x 10^-5). Pathway analysis revealed profound disruption of Fc-gamma receptor signaling (p = 3.11 x 10^-7), alongside widespread changes in immune response and synaptic organization pathways. Conclusion: These findings establish MEF2C as a master transcriptional regulator coordinating both immune effector functions and synaptic interaction programs in microglia. The observed changes, particularly in Fc receptor signaling critical for synaptic pruning, likely underlie the neurological manifestations of MEF2C syndrome. Keywords: MEF2C, microglia, ChIP-seq, RNA-seq, neurodevelopmental disorders