Regulators of the histone H3-trimethyl lysine-4 (H3K4me3) mark are significantly associated with the genetic risk architecture of common neurodevelopmental disease, including schizophrenia and autism. Typical H3K4me3 is primarily localized in the form of sharp peaks, extending in neuronal chromatin on average only across 500-1500 base pairs mostly in close proximity to annotated transcription start sites.
Here, through integrative computational analysis of epigenomic and transcriptomic data based on next-generation sequencing, researchers from the Icahn School of Medicine investigated H3K4me3 landscapes of sorted neuronal and non-neuronal nuclei in human postmortem, non-human primate and mouse prefrontal cortex (PFC), and blood. To explore whether H3K4me3 peak signals could also extend across much broader domains, the researchers examined broadest domain cell-type-specific H3K4me3 peaks in an unbiased manner with an innovative approach on ChIP-seq and RNA-seq data sets. The broadest neuronal peaks showed distinct motif signatures and were centrally positioned in prefrontal gene-regulatory Bayesian networks and sensitive to defective neurodevelopment.
Cell-type-specific histone methylation profiling in PFC. (a) Graphical outline of experiment starting with postmortem cerebral cortex (PFC) to generate cell-type-specific H3K4me3 maps. (b, c) Heatmaps for Spearman’s rank correlation coefficients comparing H3K4me3 profiles for three peripheral mononuclear blood cells (blood), two sorted NeuN− PFC cells, compared with (b) 11 PFC NeuN+ samples (cohort 1) and (c) 14 PFC NeuN+ samples (cohort 2) each from a different individual, showing much higher correlations between samples from the same cell type as compared with sample correlations across cell types and tissues. Principal component analyses showing complete separation of NeuN+ samples from other cell types with the first two principal components. (d, e) Venn diagrams showing absolute number of peaks for NeuN+, NeuN− and blood, confirming for (d) cohort 1 and (e) cohort 2 the enrichment cell-type-specific peaks among the top 5% broadest H3K4me3 peaks, as compared with the total set of peaks. (f) Venn diagram confirming that large majority of neuron-specific peaks from cohort 1 are confirmed in replication sample (cohort 2). ChIP-seq, chromatin immunoprecipitation and next-generation sequencing; H3K4me3, H3-trimethyl lysine 4; PFC, prefrontal cortex.
Approximately 120 of the broadest H3K4me3 peaks in human PFC neurons, including many genes related to glutamatergic and dopaminergic signaling, were fully conserved in chimpanzee, macaque and mouse cortical neurons. Exploration of spread and breadth of lysine methylation markings could provide novel insights into epigenetic mechanism involved in neuropsychiatric disease and neuronal genome evolution.