DC5: Enhancer responsiveness in disease models of Cornelia de Lange and Wiedemann-Steiner syndromes – CSIC

DC5 (CSIC) will investigate the molecular etiology of Cornelia de Lange syndrome (CDLS) and Wiedemann-Steiner Syndrome (WDSTS), focusing on the potential alteration of enhancer-gene communication during neural crest (NC) development. CDLS and WDSTS  are rare diseases with largely overlapping clinical features, including craniofacial dysmorphism, mental retardation and limb abnormalities. CDLS is caused by mutations in genes encoding different components of the Cohesin complex, including NIPBL, while WDSTS is caused by mutations in KDM2A/MLL.  In this project we will investigate the role of Cohesin and KMT2A/MLL in 3D genome organization and gene expression control during neural crest development using hiPSC-based in vitro differentiation systems. Since the presence of craniofacial abnormalities is a main feature of both CDLS and WDSTS, we hypothesize that, compared to other cell types, the neural crest cells might be particularly sensitive to Cohesin and KMT2A/MLL dosage. Furthermore, given the strong clinical similarities between CDLS and WDSTS, we also hypothesize that Cohesin and KMT2A/MLL might participate in similar regulatory networks and molecular processes (e.g. enhancer-gene contacts) during neural crest development. To test these hypotheses, we will combine in vitro disease modeling and genetic engineering with several genomic and computational approaches. Overall , this project will provide novel insights into how changes in enhancer-gene communication might lead  to congenital defects.