Position effects in the 3D genome as the cause of neurodevelopmental disorders

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The discovery of topologically associating domains (TADs) and our increased understanding of long-range regulation have allowed us to better understand the mechanisms underlying “position effects. Structural variants (SVs) have the potential to disrupt higher order chromatin organization thereby rewiring the complex three-dimensional chromatin organization of the locus. SVs that disrupt TAD boundaries and promoter-enhancer interactions are relatively common in skeletal malformations and certain tumors. However, the role of SVs changing the 3D genome architecture in neurodevelopmental disorders (NDDs) is less understood. In the first funding period we have successfully shown that SVs cause position effects in the 3D genome in NDDs and that HiC can effectively be used to identify SVs in patient cells. In the second funding period we now aim to functionally characterize specific deletions at the Zfp608/Lmnb1 locus and an insertion at the Sox3 locus to decipher the molecular drivers of position effects causing NDDs. In Aim 1 we will decipher the molecular drivers of 3D position effects at the Zfp608/Lmnb1 locus associated with autosomal dominant demyelinating leukodystrophy (ADLD). In Aim 2 we will dissect the molecular mechanism of an insertion at the SOX3 locus associated with spastic paraplegia and reduced SOX3 expression. And finally in Aim 3 we will map the cell type specific activity of enhancer elements located in the regulatory landscapes of Zfp608/Lmnb1 in vivo at single-cell resolution. Our data will contribute to a better understanding of the molecular biology of position effects in patients with NDDs.