Regulatory element networks in glaucoma: Elucidating the functional role of the non-coding genome during neurodegeneration

• Applicant: Dr. Felix Strübing
• Subject Area: Ophthalmology ; Experimental Models for the Understanding of Nervous System Diseases ; Medical Informatics and Medical Bioinformatics ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 491293172

Neurodegenerative disorders pose a growing threat to public health in an ever-aging society. Among these, glaucoma is an eye-related disease that results in progressive and irreversible blindness. Much research has been done to investigate the associated genetic risk factors, but only few studies have led to significant discoveries that could be translated to benefit patients. This is partly due to the fact that almost 95% of all known genetic risk factors to date are not associated with a protein-coding gene, but rather with non-coding loci that exert a regulatory effect on gene expression. Studying these non- coding “regulatory elements” (REs) used to be extremely tedious due to their complex interactions and the lack of suitable methods. However, recent advances in next-generation-sequencing applications, synthetic biology and bioinformatic analysis pipelines now enable us to functionally interrogate the non-coding genome in a highly precise and cost-efficient fashion. Here, we propose a series of experiments to elucidate the role of REs during the progression of glaucomatous neurodegeneration. We will first identify RE location and their epigenetic environment in mice. Because we and others have demonstrated a role for the immune system during neurodegeneration, we will then monitor glaucoma-related REs in vivo and in a cell type-specific way using a method that we have previously developed. Since REs have furthermore been shown to act in concert to change the expression of protein-coding genes, we will reconstruct these networks and directly relate their variants to alterations in gene expression. Thus, we will close the gap in understanding between non-coding gene mutations and disease susceptibility. Collectively, the suggested experiments should not only lead to a substantial improvement of our understanding of the non- coding genome in a highly prevalent neurodegenerative disease, but also contribute to the development of futuristic therapeutic approaches.

• DFG Programme: Research Grants