Loop Interrupted: Dysfunctional Chromatin Relations in Neurological Diseases

The majority of genetic variants for psychiatric disorders have been found within non-coding genomic regions. Physical interactions of gene promoters with distant regulatory elements carrying risk alleles may explain how the latter affect gene expression. Recently, whole genome maps of long-range chromosomal contacts from human postmortem brains have been integrated with gene sequence and chromatin accessibility data to decipher disease-specific alterations in chromatin architecture. Cell culture and rodent models provide a causal link between chromatin conformation, long-range chromosomal contacts, gene expression, and disease phenotype. Here, we give an overview of the techniques used to study chromatin contacts and their limitations in brain research. We present evidence for three-dimensional genome changes in physiological brain function and assess how its disturbance contributes to psychiatric disorders. Lastly, we discuss remaining questions and future research directions with a focus on clinical applications.