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

Eva D'haene UGent, Reut Bar-Yaakov, Inbar Bariah, Sien Van Loo, Lies Vantomme UGent, Francisco Avila Cobos UGent, Reut Eshel, Rowan Alatawna, Björn Menten UGent, Ramon Birnbaum, et al. (2018) In Keystone symposium: Gene Control in Development and Disease, Abstract book
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
conference (meetingAbstract)
publication status
published
series title
Keystone symposium: Gene Control in Development and Disease, Abstract book
conference name
Keystone symposium: Gene Control in Development and Disease
conference location
Whistler
conference start
2018-03-23
conference end
2018-03-27
UGent publication?
yes
classification
U
id
8562000
handle
http://hdl.handle.net/1854/LU-8562000
date created
2018-05-16 10:00:11
date last changed
2018-05-16 10:02:36
@inproceedings{8562000,
  abstract     = {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. 
},
  author       = {D'haene, Eva and Bar-Yaakov, Reut and Bariah, Inbar and Van Loo, Sien and Vantomme, Lies and Avila Cobos, Francisco and Eshel, Reut and Alatawna, Rowan and Menten, Bj{\"o}rn and Birnbaum, Ramon and Vergult, Sarah},
  location     = {Whistler},
  title        = {The MEF2C regulatory network is disrupted in patients with Rett-like characteristics},
  year         = {2018},
}

Chicago
D’haene, Eva, Reut Bar-Yaakov, Inbar Bariah, Sien Van Loo, Lies Vantomme, Francisco Avila Cobos, Reut Eshel, et al. 2018. “The MEF2C Regulatory Network Is Disrupted in Patients with Rett-like Characteristics.” In .
APA
D’haene, E., Bar-Yaakov, R., Bariah, I., Van Loo, S., Vantomme, L., Avila Cobos, F., Eshel, R., et al. (2018). The MEF2C regulatory network is disrupted in patients with Rett-like characteristics. Presented at the Keystone symposium: Gene Control in Development and Disease.
Vancouver
1.
D’haene E, Bar-Yaakov R, Bariah I, Van Loo S, Vantomme L, Avila Cobos F, et al. The MEF2C regulatory network is disrupted in patients with Rett-like characteristics. 2018.
MLA
D’haene, Eva, Reut Bar-Yaakov, Inbar Bariah, et al. “The MEF2C Regulatory Network Is Disrupted in Patients with Rett-like Characteristics.” 2018. Print.