Human-specific CpG 'beacons' identify human-specific prefrontal cortex H3K4me3 chromatin peaks

Targeted recruitment of chromatin-modifying enzymes to clusters of CpG dinucleotides contributes toward the formation of accessible chromatin. By interprimate comparison we previously identified the set of nonpolymorphic human-specific CpGs (CpG 'beacons') and revealed that these loci were enriched for human disease traits. Due to their human-specific CpG density change, extreme CpG 'beacon' clusters (≥20 CpG beacons/kb) were predicted to identify permissive chromatin peaks within the human genome.

We set out to explore these sequence-defined regions for evidence of an active chromatin signature.

Using available comparative primate epigenomic data from neurons of the prefrontal cortex, we show that these CpG 'beacon' clusters are indeed enriched for being human-specific H3K4me3 peaks (χ(2): p < 2.2 × 10(-16)) and thus predictive of permissive chromatin states. These sequence regions had a higher predictive value than previous selective analyses. We also show that both human-specific H3K4me3 and CpG 'beacon' clusters are increased within current and ancestral telomeric regions, supporting an association with recombination, which is higher towards the distal ends of chromosomes.

Therefore, CpG-focused comparative sequence analysis can precisely pinpoint chromatin structures that contribute to the human-specific phenotype and further supports an integrated approach in genomic and epigenomic studies.