Abstract
The non-coding genome, consisting of more than 98% of all genetic information in humans and once judged as ‘Junk DNA’, is increasingly moving into the spotlight in the field of human genetics. Non-coding regulatory elements (NCREs) are crucial to ensure correct spatio-temporal gene expression. Technological advancements have allowed to identify NCREs on a large scale, and mechanistic studies have helped to understand the biological mechanisms underlying their function. It is increasingly becoming clear that genetic alterations of NCREs can cause genetic disorders, including brain diseases. In this review, we concisely discuss mechanisms of gene regulation and how to investigate them, and give examples of non-coding alterations of NCREs that give rise to human brain disorders. The cross-talk between basic and clinical studies enhances the understanding of normal and pathological function of NCREs, allowing better interpretation of already existing and novel data. Improved functional annotation of NCREs will not only benefit diagnostics for patients, but might also lead to novel areas of investigations for targeted therapies, applicable to a wide panel of genetic disorders. The intrinsic complexity and precision of the gene regulation process can be turned to the advantage of highly specific treatments. We further discuss this exciting new field of ‘enhancer therapy’ based on recent examples.
Highlights
The human genome contains more than 20,000 protein-coding genes whose expression needs to be precisely regulated in order for normal development and physiology to occur
that is linked to non-coding variants
the first therapies targeted to non-coding regulatory element (NCRE) are being developed
Summary
The human genome contains more than 20,000 protein-coding genes whose expression needs to be precisely regulated in order for normal development and physiology to occur. Other techniques include methods that study the genome-wide interactions of selected regions of interest (such as promoter capture Hi-C [40]) or targets bound by a protein of interest (such as HiChIP [41]) Together, these and other approaches allow to map chromatin conformation interactions, and the knowledge obtained from this can be used to predict the location of putative enhancers. As EDS correlates variations in regulatory regions with phenotypic effects, it could be used as a tool to find the most clinically relevant enhancers and complement other methods which measure the importance of dosage-sensitive genes This approach integrated with open chromatin data in iPSC-derived neurons revealed potential causative variants of schizophrenia which influenced chromatin accessibility [91]. This elegantly illustrates how similar approaches could be designed for other genetic disorders, including those affecting the neurvous system
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