Project Details
Projekt
Epigenomic mapping of myogenic regulation in human muscle development
Applicant
Professor Dr.-Ing. Uwe Ohler
Subject Area
Human Genetics
Bioinformatics and Theoretical Biology
Developmental Biology
Bioinformatics and Theoretical Biology
Developmental Biology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 400728090
Congenital myopathies and congenital muscle dystrophies are a group of genetic muscle disorders clinically characterized by muscle hypotonia and weakness and a static or slowly progressive clinical course. Widespread use of Whole Exome Sequencing (WES) over the course of the last decade has led to the identification of the underlying genetic cause of many different congenital myopathies muscular dystrophies, but a large subset of these cases has eluded all attempts to make a molecular diagnosis. We focused on a Charité cohort of patients with congenital myopathy and muscular dystrophy in whom WES had found no genetic cause in protein coding sequences and set out to find disease-causing variants in the non-coding or regulatory sequences of the genome. These regions, which harbor enhancers and transcription factor binding sites (TFBSs), control muscle-specific gene expression programs whose dysfunction is the cause of pathogenesis. In our collaborative research program, we have embarked on a series of comprehensive epigenomic and transcriptional bulk and single-cell analyses of successive developmental stages of muscle cell differentiation. At the same time, we have developed computational models for multimodal data integration. Building on this work from the first funding period, we will now develop computational approaches to classify distinct enhancer subgroups and to identify relevant DNA sequence information within myogenic regulatory regions. We will use these models to identify variants predicted to alter the transcriptional programs in patients with congenital myopathy. We will validate the impact of dozens of enhancer candidates, as well as sequence variations on target gene expression using CRISPRi/a screens, and finally confirm the impact of non-coding variation on differentiation. In this way, our project will enable the translation of the basic molecular biology into diagnoses for patients with rare muscle diseases.
DFG Programme
Research Units
