Elucidating the role of cis-regulation and of ultraconserved non-coding elements associated with the choroideremia gene CHM

The human genome is partitioned in functional building blocks, so-called topologically associating
domains (TADs). Within TADs, genes and non-coding cis-regulatory elements (CREs) physically interact with each other more frequently than with elements outside the TAD. CREs need to be
intact for a correct time and tissue specific gene expression. Some TADs also contain
ultraconserved non-coding elements (UCNEs), assumed to have a role during development.
Despite the importance of CREs and UCNEs in development and disease, there is still limited
knowledge on their location, target genes and function. Here, we focus on closing the knowledge
gap on the regulation of the CHM gene, which is implicated in choroideremia, a monogenic
blinding condition which is amenable to gene therapy. The general aim is to identify CREs and
UCNEs involved in the regulation of CHM in the retina and to assess their role in choroideremia
pathogenesis, since these elements are potential targets for non-coding defects, contributing to
missing heritability in this disease. Specifically, we will first characterize the cis-regulatory
landscape of the CHM region in human retinal cells, followed by the functional characterization of
the identified CREs and UCNEs using CRISPR/Cas9-based genome editing in both a cellular and a
Xenopus model. Overall, this study will serve as a basis for better understanding the drivers of
CHM regulation and has the potential to be expanded to other (retinal) disease genes.