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The MEF2C regulatory network is disrupted in patients with Rett-like characteristics

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Abstract
Myocyte enhancer factor 2C (MEF2C) is a core transcription factor in neurodevelopment. In the context of human disease, MEF2C haploinsufficiency has been associated with a Rett-like syndrome, characterized by severe intellectual disability, seizures and stereotypic movements. Chromosomal aberrations in the MEF2C region, some of which do not encompass MEF2C itself, have been associated with a similar Rett-like phenotype. So far, 11 deletions, eight translocations and one inversion involving 5q14.3 in Rett-like patients have been described, that do not directly affect the MEF2C coding sequence, suggesting that disruption of MEF2C regulatory elements could result in this Rett-like syndrome. The MEF2C regulatory network, however, is yet to be deciphered. To shed light on the regulatory interactions governing neuronal MEF2C transcription, we performed Circularized Chromosome Conformation Capture (4C) sequencing and characterized the activity of putative, neuronal MEF2C enhancers using in vitro and in vivo enhancer assays. Through extensive 4C sequencing in a neuronal cell line, we revealed an intricate interaction network, in which the MEF2C promoter physically contacts distal putative enhancers located in the region affected in Rett-like patients. We confirmed enhancer potential for 10 out of 15 selected candidate elements using luciferase assays. Moreover, eight candidate enhancers exhibited in vivo neuronal activity in zebrafish. Six of these were active in the forebrain, of which three also displayed additional activity in specific neurons above the eye and two in the notochord. Further, one enhancer displayed mid- and hindbrain activity and one was specifically active in the notochord. Interestingly, we also identified three enhancers with specific activity in the heart. This is not surprising, as MEF2C is known to be involved in heart development as well. In summary, we have begun to unravel a complex regulatory network governing neuronal 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.

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Chicago
D’haene, Eva, Sarah Vergult, Reut Bar-Yaakov, Inbar Bariah, Lies Vantomme, Sien Van Loo, Francisco Avila Cobos, et al. 2018. “The MEF2C Regulatory Network Is Disrupted in Patients with Rett-like Characteristics.” In Belgian Society for Human Genetics, 18th Annual Meeting, Abstracts.
APA
D’haene, E., Vergult, S., Bar-Yaakov, R., Bariah, I., Vantomme, L., Van Loo, S., Avila Cobos, F., et al. (2018). The MEF2C regulatory network is disrupted in patients with Rett-like characteristics. Belgian Society for Human Genetics, 18th Annual meeting, Abstracts. Presented at the 18th Annual BeSHG meeting: The epigenome in development and disease.
Vancouver
1.
D’haene E, Vergult S, Bar-Yaakov R, Bariah I, Vantomme L, Van Loo S, et al. The MEF2C regulatory network is disrupted in patients with Rett-like characteristics. Belgian Society for Human Genetics, 18th Annual meeting, Abstracts. 2018.
MLA
D’haene, Eva, Sarah Vergult, Reut Bar-Yaakov, et al. “The MEF2C Regulatory Network Is Disrupted in Patients with Rett-like Characteristics.” Belgian Society for Human Genetics, 18th Annual Meeting, Abstracts. 2018. Print.
@inproceedings{8561993,
  abstract     = {Myocyte enhancer factor 2C (MEF2C) is a core transcription factor in neurodevelopment. In the context of human disease, MEF2C haploinsufficiency has been associated with a Rett-like syndrome, characterized by severe intellectual disability, seizures and stereotypic movements. Chromosomal aberrations in the MEF2C region, some of which do not encompass MEF2C itself, have been associated with a similar Rett-like phenotype. So far, 11 deletions, eight translocations and one inversion involving 5q14.3 in Rett-like patients have been described, that do not directly affect the MEF2C coding sequence, suggesting that disruption of MEF2C regulatory elements could result in this Rett-like syndrome. The MEF2C regulatory network, however, is yet to be deciphered. To shed light on the regulatory interactions governing neuronal MEF2C transcription, we performed Circularized Chromosome Conformation Capture (4C) sequencing and characterized the activity of putative, neuronal MEF2C enhancers using in vitro and in vivo enhancer assays.
Through extensive 4C sequencing in a neuronal cell line, we revealed an intricate interaction network, in which the MEF2C promoter physically contacts distal putative enhancers located in the region affected in Rett-like patients. We confirmed enhancer potential for 10 out of 15 selected candidate elements using luciferase assays. Moreover, eight candidate enhancers exhibited in vivo neuronal activity in zebrafish. Six of these were active in the forebrain, of which three also displayed additional activity in specific neurons above the eye and two in the notochord.  Further, one enhancer displayed mid- and hindbrain activity and one was specifically active in the notochord. Interestingly, we also identified three enhancers with specific activity in the heart. This is not surprising, as MEF2C is known to be involved in heart development as well.
In summary, we have begun to unravel a complex regulatory network governing neuronal 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.},
  author       = {D'haene, Eva and Vergult, Sarah and Bar-Yaakov, Reut and Bariah, Inbar and Vantomme, Lies and Van Loo, Sien and Avila Cobos, Francisco and Eshel, Reut and Alatawna, Rowan and Birnbaum, Ramon and Menten, Bj{\"o}rn},
  booktitle    = {Belgian Society for Human Genetics, 18th Annual meeting, Abstracts},
  language     = {eng},
  location     = {Ghent, Belgium},
  title        = {The MEF2C regulatory network is disrupted in patients with Rett-like characteristics},
  year         = {2018},
}