Advances in profiling chromatin architecture shed light on the regulatory dynamics underlying brain disorders

Understanding the exquisitely complex nature of the three-dimensional organization of the genome and how it affects gene regulation remains a central question in biology. Recent advances in sequencing- and imaging-based approaches in decoding the three-dimensional chromatin landscape have enabled a systematic characterization of gene regulatory architecture. In this review, we outline how chromatin architecture provides a reference atlas to predict the functional consequences of non-coding variants associated with human traits and disease. Highthroughput perturbation assays such as massively parallel reporter assays (MPRA) and CRISPR-based genome engineering in combination with a reference atlas opened an avenue for going beyond observational studies to experimentally validating the regulatory principles of the genome. We conclude by providing a suggested path forward by calling attention to barriers that can be addressed for a more complete understanding of the regulatory landscape of the human brain.

Automated summary

This review discusses the importance of understanding the three-dimensional organization of the genome and its impact on gene regulation. It highlights how chromatin architecture can be used as a reference atlas to predict the functional consequences of non-coding variants associated with human traits and diseases. The use of high-throughput perturbation assays in combination with a reference atlas allows for experimental validation of the regulatory principles of the genome.