Myocyte enhancer factor 2C (MEF2C) is a core transcription factor in neurodevelopment. In the context of human disease, MEF2C mutations have primarily been associated with a severe intellectual disability syndrome that shows phenotypical overlap with Rett syndrome, a progressive neurodevelopmental disorder featured by severe mental retardation, seizures and hypotonia. Recently, several patients with a similar Rett-like phenotype have been identified that harbour structural variants (SVs) upstream of MEF2C, but not encompassing the MEF2C coding sequence itself. This suggests that alteration of regulatory interactions could play a role in this Rett-like phenotype. However, the MEF2C regulatory network is yet to be deciphered. Therefore, we dissected the MEF2C region, using Circularized Chromosome Conformation Capture (4C) sequencing, in vitro and in vivo enhancer assays. Mining literature and public variant databases, we found 11 deletions, 8 translocations and one inversion in the MEF2C regulatory region that do not directly affect the MEF2C coding sequence itself. Extensive 4C sequencing revealed an interaction network, in which the MEF2C promoter physically contacts distal, putative enhancers, located in the region affected in these patients. Using luciferase assays, we confirmed enhancer potential for 9 out of 15 selected candidate elements. Furthermore, using in vivo zebrafish enhancer assays, we showed that several elements have neuronal activity in the developing zebrafish. Five enhancers showed activity in the forebrain, three in specific neurons above the eye and one in the notochord. Interestingly, three enhancers also showed specific activity in the heart. This is not surprising, as MEF2C is also well known to be involved in heart development. In summary, we started to disentangle a complex regulatory network governing MEF2C transcription, that involves multiple distal enhancers. Disrupting this regulatory structure is likely detrimental to normal neurodevelopment and can give rise to neurodevelopmental disorders such as Rett-like syndrome.
|Conference||Keystone symposium on Molecular and Cellurlar Biology: Gene control in development and disease|
|Period||23/03/18 → 27/03/18|