Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models
- Author
- Kiana Mohajeri, Rachita Yadav, Eva D'haene (UGent) , Philip M. Boone, Serkan Erdin, Dadi Gao, Mariana Moyses-Oliveira, Riya Bhavsar, Benjamin B. Currall, Kathryn O'Keefe, Nicholas D. Burt, Chelsea Lowther, Diane Lucente, Monica Salani, Mathew Larson, Claire Redin, Olga Dudchenko, Erez Lieberman Aiden, Björn Menten (UGent) , Derek J.C. Tai, James F. Gusella, Sarah Vergult (UGent) and Michael E. Talkowski
- Organization
- Project
-
- Unraveling the role of MYT1L in intellectual disability: an integrated functional genetic approach
- Functional validation of cis-regulatory elements of respectively MEF2C and FOXG1
- Dissecting the regulatory landscape of MEF2C and FOXG1 in Rett-like manifestations
- The role of lncRNAs in human cognition
- Abstract
- Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with structural variants that alter MEF2C expression and/or regulation, we generated an allelic series of 204 isogenic human induced pluripotent stem cell (hiPSC)-derived neural stem cells and glutamatergic induced neurons. These neuronal models harbored CRISPR-engineered mutations that involved direct deletion of MEF2C or deletion of the boundary points for topologically associating domains (TADS) and chromatin loops encompassing MEF2C. Systematic profiling of mutation-specific alterations, contrasted to unedited controls that were exposed to the same guide RNAs for each edit, revealed that deletion of MEF2C caused differential expression of genes associated with neurodevelopmental pathways and synaptic function. We also discovered significant reduction in synaptic activity measured by multielectrode arrays (MEAs) in neuronal cells. By contrast, we observed robust buffering against MEF2C regulatory disruption following deletion of a distal 5g14.3 TAD and loop boundary, whereas homozygous loss of a proximal loop boundary resulted in down-regulation of MEF2C expression and reduced electrophysiological activity on MEA that was comparable to direct gene disruption. Collectively, these studies highlight the considerable functional impact of MEF2C deletion in neuronal cells and systematically characterize the complex interactions that challenge a priori predictions of regulatory consequences from structural variants that disrupt three-dimensional genome organization.
- Keywords
- Genetics (clinical), Genetics
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Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01GV69E6J20TGKBFVAAG4M3CJV
- MLA
- Mohajeri, Kiana, et al. “Transcriptional and Functional Consequences of Alterations to MEF2C and Its Topological Organization in Neuronal Models.” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 109, no. 11, Elsevier BV, 2022, pp. 2049–67, doi:10.1016/j.ajhg.2022.09.015.
- APA
- Mohajeri, K., Yadav, R., D’haene, E., Boone, P. M., Erdin, S., Gao, D., … Talkowski, M. E. (2022). Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models. AMERICAN JOURNAL OF HUMAN GENETICS, 109(11), 2049–2067. https://doi.org/10.1016/j.ajhg.2022.09.015
- Chicago author-date
- Mohajeri, Kiana, Rachita Yadav, Eva D’haene, Philip M. Boone, Serkan Erdin, Dadi Gao, Mariana Moyses-Oliveira, et al. 2022. “Transcriptional and Functional Consequences of Alterations to MEF2C and Its Topological Organization in Neuronal Models.” AMERICAN JOURNAL OF HUMAN GENETICS 109 (11): 2049–67. https://doi.org/10.1016/j.ajhg.2022.09.015.
- Chicago author-date (all authors)
- Mohajeri, Kiana, Rachita Yadav, Eva D’haene, Philip M. Boone, Serkan Erdin, Dadi Gao, Mariana Moyses-Oliveira, Riya Bhavsar, Benjamin B. Currall, Kathryn O’Keefe, Nicholas D. Burt, Chelsea Lowther, Diane Lucente, Monica Salani, Mathew Larson, Claire Redin, Olga Dudchenko, Erez Lieberman Aiden, Björn Menten, Derek J.C. Tai, James F. Gusella, Sarah Vergult, and Michael E. Talkowski. 2022. “Transcriptional and Functional Consequences of Alterations to MEF2C and Its Topological Organization in Neuronal Models.” AMERICAN JOURNAL OF HUMAN GENETICS 109 (11): 2049–2067. doi:10.1016/j.ajhg.2022.09.015.
- Vancouver
- 1.Mohajeri K, Yadav R, D’haene E, Boone PM, Erdin S, Gao D, et al. Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models. AMERICAN JOURNAL OF HUMAN GENETICS. 2022;109(11):2049–67.
- IEEE
- [1]K. Mohajeri et al., “Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 109, no. 11, pp. 2049–2067, 2022.
@article{01GV69E6J20TGKBFVAAG4M3CJV,
abstract = {{Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with structural variants that alter MEF2C expression and/or regulation, we generated an allelic series of 204 isogenic human induced pluripotent stem cell (hiPSC)-derived neural stem cells and glutamatergic induced neurons. These neuronal models harbored CRISPR-engineered mutations that involved direct deletion of MEF2C or deletion of the boundary points for topologically associating domains (TADS) and chromatin loops encompassing MEF2C. Systematic profiling of mutation-specific alterations, contrasted to unedited controls that were exposed to the same guide RNAs for each edit, revealed that deletion of MEF2C caused differential expression of genes associated with neurodevelopmental pathways and synaptic function. We also discovered significant reduction in synaptic activity measured by multielectrode arrays (MEAs) in neuronal cells. By contrast, we observed robust buffering against MEF2C regulatory disruption following deletion of a distal 5g14.3 TAD and loop boundary, whereas homozygous loss of a proximal loop boundary resulted in down-regulation of MEF2C expression and reduced electrophysiological activity on MEA that was comparable to direct gene disruption. Collectively, these studies highlight the considerable functional impact of MEF2C deletion in neuronal cells and systematically characterize the complex interactions that challenge a priori predictions of regulatory consequences from structural variants that disrupt three-dimensional genome organization.}},
author = {{Mohajeri, Kiana and Yadav, Rachita and D'haene, Eva and Boone, Philip M. and Erdin, Serkan and Gao, Dadi and Moyses-Oliveira, Mariana and Bhavsar, Riya and Currall, Benjamin B. and O'Keefe, Kathryn and Burt, Nicholas D. and Lowther, Chelsea and Lucente, Diane and Salani, Monica and Larson, Mathew and Redin, Claire and Dudchenko, Olga and Aiden, Erez Lieberman and Menten, Björn and Tai, Derek J.C. and Gusella, James F. and Vergult, Sarah and Talkowski, Michael E.}},
issn = {{0002-9297}},
journal = {{AMERICAN JOURNAL OF HUMAN GENETICS}},
keywords = {{Genetics (clinical),Genetics}},
language = {{eng}},
number = {{11}},
pages = {{2049--2067}},
publisher = {{Elsevier BV}},
title = {{Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models}},
url = {{http://doi.org/10.1016/j.ajhg.2022.09.015}},
volume = {{109}},
year = {{2022}},
}
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