Coordinated Cell Type–Specific Epigenetic Remodeling in Prefrontal Cortex Begins before Birth and Continues into Early Adulthood

Abstract

Development of prefrontal and other higher-order association cortices is associated with widespread changes in the cortical transcriptome, particularly during the transitions from prenatal to postnatal development, and from early infancy to later stages of childhood and early adulthood. However, the timing and longitudinal trajectories of neuronal gene expression programs during these periods remain unclear in part because of confounding effects of concomitantly occurring shifts in neuron-to-glia ratios. Here, 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. Developmentally downregulated H3K4me3 peaks in prefrontal neurons were enriched for Paired box (Pax) and multiple Signal Transducer and Activator of Transcription (STAT) motifs, which are known to promote glial differentiation. In contrast, H3K4me3 peaks subject to a progressive increase in maturing prefrontal neurons were enriched for activating protein-1 (AP-1) recognition elements that are commonly associated with activity-dependent regulation of neuronal gene expression. We uncovered a developmental program governing the remodeling of neuronal histone methylation landscapes in the prefrontal cortex from the late prenatal period to early adolescence, which is linked to cis-regulatory sequences around transcription start sites. Prolonged maturation of the human cerebral cortex, which extends into the third decade of life, is critical for proper development of executive functions such as higher-order problem-solving and complex cognition. Little is known about changes of post-mitotic neurons during this prolonged maturation period, including changes in epigenetic regulation, and more broadly, in genome organization and function. Such knowledge is critical for a deeper understanding of human development, cognitive abilities, and psychiatric diseases. Here, we identify 1,157 genomic loci in neuronal cells from the prefrontal cortex that show developmental changes in a chromatin mark, histone H3 trimethylated at lysine 4 (H3K4me3), which has been associated with regulation of gene expression. Interestingly, the overwhelming majority of these developmentally regulated H3K4me3 peaks were defined by rapid gain or loss of histone methylation during the late prenatal period and the first year after birth, followed by slower changes during early and later childhood and minimal changes thereafter. The genomic sequences showing these dynamic changes in H3K4me3 were enriched with distinct transcription factor motifs. Our findings suggest that there is highly regulated, pre-programmed remodeling of neuronal histone methylation landscapes in the human brain that begins before birth and continues into adolescence.