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Hum Mol Genet. 2018 Nov 15. doi: 10.1093/hmg/ddy393. [Epub ahead of print]

A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics.

Author information

1
Center for Medical Genetics, Ghent University, Belgium.
2
Department of Life Sciences, Faculty of Natural Sciences, The Ben-Gurion University of the Negev, Israel.
3
Center of Evolutionary Genomics and Medicine, The Ben-Gurion University of the Negev, Israel.
4
Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
5
Bioinformatics Institute Ghent from Nucleotides to Networks (BIG N2N), Ghent, Belgium.

Abstract

Mutations in myocyte enhancer factor 2C (MEF2C), an important transcription factor in neurodevelopment, are associated with a Rett-like syndrome. Structural variants (SVs) upstream of MEF2C, that do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype. To characterize those elements that regulate MEF2C during neural development and which are affected by these SVs, we used genomic tools coupled with both in vitro and in vivo functional assays. Through 4C-seq and ATAC-seq, we revealed a complex interaction network in which the MEF2C promoter physicallycontacts several distal enhancers that are deleted or translocated by disease-associated SVs. Sixteen selected candidate regulatory sequences were tested for enhancer activity in vitro, with fourteen found to be functional enhancers. Further analyses of their in vivo activity in zebrafish showed that each of these enhancers has a distinct activity pattern during development, with eight enhancers displaying neuronal activity. In summary, our results disentangle a complex regulatory network governing neuronalMEF2Cexpression that involves multiple distal enhancers. In addition, the characterized neuronal enhancers pose as novel candidates to screen for mutations in neuro developmental disorders, such as Rett-likesyndrome.

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