Role of the ultraconserved IRXA cluster in North Carolina Macular Dystrophy, a retinal enhanceropathy

01 November 2023 → 31 October 2027
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Developmental genetics
    • Genome structure and regulation
  • Medical and health sciences
    • Genetics
    • Stem cell biology
    • Ophtalmology
Retinal organoids Multi-omics profiling Retinal enhanceropathy
Project description

Since the landmark study of Bejerano et al. (2004) about the paradoxical function of ultraconserved non-coding elements (UCNEs), their role in development and disease is still poorly understood. A recent example of an ultraconserved genomic region implicated in human disease, are duplications of a gene desert downstream of the IRXA cluster, found in patients with North Carolina Macular Dystrophy (NCMD). NCMD is a rare autosomal dominant developmental maculopathy impairing central vision. The shared duplicated region harbours a UCNE that is a candidate cis-regulatory element (cCRE) during macular development. Although we have recently provided evidence that NCMD is a retinal enhanceropathy, no NCMD disease models have been investigated so far, however. The general aim of this study is to dissect the mechanism underlying IRXA-associated NCMD. Key objectives are (1) to functionally validate tissue-specific cCREs of the ultraconserved IRXA cluster using CRISPRi perturbation; (2) to establish patient-derived disease models for IRXA-associated NCMD; (3) to assess the impact of a dysregulated IRXA cluster on 3D topology using chromatin interaction profiling and (4) on gene expression and regulatory networks using bulk and single-cell transcriptomics. By elucidating the molecular pathways and regulatory networks impaired in IRXA-associated NCMD, we will gain insight into the role of this ultraconserved cluster in human macular development and disease.