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Am J Hum Genet DOI:10.1016/j.ajhg.2022.09.015

Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models.

Publication TypeJournal Article
Year of Publication2022
AuthorsMohajeri, K, Yadav, R, D'haene, E, Boone, PM, Erdin, S, Gao, D, Moyses-Oliveira, M, Bhavsar, R, Currall, BB, O'Keefe, K, Burt, ND, Lowther, C, Lucente, D, Salani, M, Larson, M, Redin, C, Dudchenko, O, Aiden, ELieberman, Menten, B, Tai, DJC, Gusella, JF, Vergult, S, Talkowski, ME
JournalAm J Hum Genet
Date Published2022 Oct 19
ISSN1537-6605
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 5q14.3 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.

DOI10.1016/j.ajhg.2022.09.015
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36283406?dopt=Abstract

Alternate JournalAm J Hum Genet
PubMed ID36283406