University of Massachusetts Medical School
Epigenomics of Human Prefrontal Cortex Neurons
Development of prefrontal and other higher-order association cortices is associated with widespread changes in the cortical transcriptome, and this processes may be altered in psychiatric diseases. We used cell type-specific chromatin sorting techniques for genome-wide profiling of a histone mark associated with transcriptional regulation–H3 with trimethylated lysine 4 (H3K4me3)–in neuronal chromatin from 31 subjects from the late gestational period to 80 years of age. H3K4me3 landscapes of prefrontal neurons were developmentally regulated at 1,157 loci, including 768 loci that were proximal to transcription start sites. Multiple algorithms consistently revealed that the overwhelming majority and perhaps all of developmentally regulated H3K4me3 peaks were on a unidirectional trajectory defined by either rapid gain or loss of histone methylation during the late prenatal period and the first year after birth, followed by similar changes but with progressively slower kinetics during early and later childhood and only minimal changes later in life. We compared H3K4me3 profiles between neurons from individuals afflicted with autism spectrum disorders and controls. We also studied the evolution of H3K4me3 profiles in prefrontal cortex neurons by comparing humans with chimps and macaque monkeys.