THE GENOME IN 3D: A NEW FRONTIER IN HUMAN BRAIN RESEARCH

Less than 1.5% of the human genome encodes protein. However, vast portions of the human genome are subject to transcriptional and epigenetic regulation and many non-coding regulatory DNA elements are thought to regulate the spatial organization of interphase chromosomes. For example, chromosomal ‘loopings’ are pivotal for the orderly process of gene expression, by enabling distal regulatory enhancer or silencer elements to directly interact with proximal promoter and transcription start sites, potentially bypassing hundreds of kilobases of interspersed sequence on the linear genome. To date, however, epigenetic studies in the human brain are mostly limited to the exploration of DNA methylation and posttranslational modifications of the nucleosome core histones. In contrast, very little is known about the regulation of supranucleosomal structures in brain nuclei. Here, we show that chromosome conformation capture (3C), a widely used approach to study higher order chromatin, is applicable to tissue collected postmortem, thereby informing about genome organization in the human brain. We introduce 3C protocols for brain, and compare higher order chromatin structures at the chromosome 6p22.2–22.1 schizophrenia and bipolar susceptibility locus and neurodevelopmental risk genes ( DPP10, MCPH1 ) in adult prefrontal cortex and various cell culture systems, including neurons derived from reprogrammed skin cells. We predict that the exploration of three-dimensional genome architectures and function will open up new frontiers in human brain research and psychiatric genetics, and provide novel insights into the epigenetic risk architectures of regulatory non-coding DNA.