Epigenetic regulators are preferentially coordinated with protocadherin gene expression across the human brain: a...

How does the brain build and maintain the precise wiring patterns that distinguish one neuron from another? Clustered protocadherins (PCDHs)-a family of cell-surface molecules that give each neuron a unique identity tag-are central to this process. Their expression is famously controlled by an elaborate locus-specific epigenetic system involving DNA methylation, CTCF binding, and chromatin looping. Whether the activity of the broader epigenetic regulatory machinery is coordinated with protocadherin expression across the human brain has not been systematically tested. Here we show that epigenetic regulators are preferentially co-expressed with protocadherins across multiple human brain regions, suggesting a broader transcriptional coordination than the locus-specific mechanisms previously characterized. Using GTEx v8 RNA-seq data from 2,642 brain samples across 13 regions, we conducted a genome-wide co-expression screen and observed a 6.5-fold enrichment of epigenetic regulators in the top 5% of PCDH-coordinated genes in prefrontal cortex (Fisher's exact p = 2.8 × 10^-10). The enrichment replicated independently across additional brain regions, persisted under multiple sensitivity analyses, was preserved after adjustment for cell-type composition, and replicated in an independent brain-bank cohort. The top-ranked epigenetic regulators converge on a defined set of chromatin-remodeling genes implicated in well-characterized neurodevelopmental syndromes. These findings reframe protocadherin biology by extending its epigenetically coordinated context beyond the locus itself to a broader transcriptional program shared with the chromatin-remodeling machinery associated with neurodevelopmental disease. The conceptual advance is consistent with-though does not by itself establish-direct co-regulation, and identifies a specific set of testable mechanistic hypotheses for how disrupted chromatin-remodeling activity in neurodevelopmental disorders may propagate to PCDH-dependent neuronal identity programs in the human brain.