The 3d Genome As A New Dimension In Understanding Pathologic Short Tandem Repeat Instability
Unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs) serves as the mechanistic basis for more than 25 inherited human disorders. Patients with unstable repeat expansion diseases suffer from a complex array of symptoms, including: cardiac defects, cataracts, anxiety, hyperactivity, low IQ, social deficits, respiratory defects and seizures. In some diseases, such as Fragile X Syndrome and Friedreich’s Ataxia, the downstream phenotype is mediated in large part by reduced gene expression. In all of these diseases, continuous repeat expansion is associated with disease severity. Treating trinucleotide repeat disorders is thus complex because the drivers of disease can include both the continuous expansion of repetitive sequences as well as other genome dysfunction such as disrupted expression of the gene containing the repeat. Recently, the spatial positioning of chromatin in 3D space has emerged as a precisely regulated process that has functional consequences for development and disease. Given that repeat expansion occurs within the context of ordered chromatin, 3D genome folding may introduce a new perspective from which to understand repeat expansion mediated disorders. Currently, little is known regarding how higher-order folding of chromatin in the 3D nucleus influence stability of the repetitive genome and consequences of expansion. In this work, we introduce for the first time that higher order chromatin architecture is a crucial new dimension in understanding the molecular mechanisms governing STR instability and expansion related gene dysregulation in repeat expansion disorders. Our data shows that (1) the large majority of disease associated STRs are located precisely at boundaries demarcating 3D genome folding domains termed topologically associating domains (TADs) and subTADs and (2) repeat expansion in the FMR1 gene, the genetic driver for Fragile X Syndrome, results in grossly mis-wired genome folding genome-wide and at the boundary encompassing the FMR1 gene in a manner that correlates with transcriptional disruption of FMR1 and other important genes. The implications of this work are twofold. First, we introduce a unifying framework for studying unstable repeat expansion disorders as a group, suggesting that the 3D genome is a crucial commonality to a diverse group disorders. Second, our work suggests for the first time that Fragile X Syndrome is a disease that occurs due to a genome-wide, coordinated, repressive state mediated by the 3D genome. This is in stark contrast to the current understanding of FXS as a disease due to local epigenetic silencing. In sum, we demonstrate that the 3D genome can be perturbed in repeat expansion disorders and that this perturbation can mediate repeat instability and transcriptional dysregulation. The implications of this work bring evidence to a novel potential therapeutic hypothesis, setting the stage for determining whether manipulating the 3D genome could be a potential therapeutic target for treating these diseases.