The impact of a cohesin complex on human head and face development.

• Applicant: Dr. Magdalena Laugsch, Ph.D.
• Subject Area: Human Genetics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467367413

Cornelia de Lange Syndrome (CdLS) is a rare but severe genetic disorder characterized by malformations of the head, face and limbs, heart defects, and cognitive deficits. Abnormalities in cohesin, a protein complex that regulates the separation of DNA during cell division, alter the three-dimensional structure of chromatin (a protein-associated, compacter form of DNA) and impact the regulation of gene transcription, ultimately causing CdLS. The exact molecular mechanism underlying these alterations, however, is not entirely determined yet. A large set of head and face (craniofacial) abnormalities observed in CdLS patients most likely arises during embryonic development of the neural crest. However, the relationship between the cohesin mutations and the neural crest cell development has not been investigated, although the head and face abnormalities are essential aspects of the CdLS diagnosis. Thus, based on our expertise and our preliminary work, we aim to investigate the underlying molecular defects in the neural crest cells. As the neural crest appears only transiently during embryogenesis, we will use human induced pluripotent stem cells, differentiate them towards neural crest cells, and study that process. Combining genetic and epigenetic tools, we will identify the three-dimensional structure of chromatin and regulatory networks controlled by cohesin. Then, we will apply advanced bioinformatics to investigate if mutations or other alterations of the identified regulatory network (1) are linked to undiagnosed cases of individuals with craniofacial deformities (2) are risk factors for multifactorial diseases (3) constitute to the variability of a phenotype. Outcomes of this work will expand our understanding of the genetic basis of CdLS, leading to potential improvements in diagnosis and therapy. Insights will reveal novel research paths for other disorders associated with neural crest and craniofacial abnormalities. Our team is uniquely positioned to successfully establish this novel research approach as a powerful framework to investigate the molecular basis of CdLS.

• DFG Programme: Research Grants