ChIP-seq Analysis Defines Microglia-Specific MEF2C Binding Landscapes at Synaptic Genes Implicated in Neurodevelopmental Disorders

This manuscript details a computational study investigating the role of the transcription factor MEF2C in microglia, the brain's resident immune cells. Our motivation stems from the clinical observation that MEF2C haploinsufficiency causes a severe syndromic neurodevelopmental disorder, yet the underlying mechanisms in the brain, particularly in non-neuronal cells, remain poorly defined. While MEF2C is a well-known regulator of cardiac development, we hypothesized that its functions in microglia might be critically distinct and relevant to the neurological symptoms seen in patients.

To identify potential direct transcriptional targets of MEF2C in microglia, we performed a ChIP-seq analysis on publicly available data from isogenic human iPSC-derived microglia. Our analysis revealed 1,258 significant MEF2C binding peaks associated with 1,148 genes. Intriguingly, rather than being enriched for classic immune pathways, these genes showed a strong functional signature for synaptic processes, such as "vesicle-mediated transport in synapse" and the "synaptic vesicle cycle." This immediately suggested to us that MEF2C might be involved in regulating how microglia interact with and potentially prune synapses.

This cell-type specificity was further underscored when we compared our results to MEF2C binding patterns in other tissues like cardiomyocytes and monocytes; the overlap was minimal, indicating substantial genomic reprogramming. Delving deeper, our network analysis positioned ANK3 as a putative central hub within a larger synaptic organization module. Perhaps most striking was the disease integration analysis, which showed a dramatic enrichment—over 80-fold—for genes already implicated in synaptopathies and other neurodevelopmental disorders. This allowed us to pinpoint several high-confidence candidate genes, including ANK3, DSCAM, and ARID1B, as direct MEF2C targets in microglia.

In summary, our findings provide a new, testable model for MEF2C syndrome pathogenesis. We propose that the disorder may arise not only from neuronal defects but also from a disruption in microglial function, specifically in their ability to properly refine neural circuits through synaptic pruning. This work shifts the perspective on MEF2C's role in the brain and opens up new avenues for exploring therapeutic strategies.

Keywords: MEF2C, ChIP-seq, Microglia, Neurodevelopmental Disorders, Synaptic Pruning, Transcriptional Regulation, Bioinformatics, Computational Biology, Autism Spectrum Disorder.