Evidence map›Paper›PMID 36283406›Full record

ArticleAmerican journal of human genetics2022

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

Kiana Mohajeri, Rachita Yadav, Eva D'haene, Philip M Boone, Serkan Erdin, Dadi Gao, Mariana Moyses-Oliveira, Riya Bhavsar, Benjamin B Currall, Kathryn O'Keefe and 13 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed
2.3field-weighted citation impact, top 11% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 27 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Review
  7. CRISPR-engineered deletion ofbioRxiv : the preprint server for biology · 2025
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  10. Multi-omic analysis of the ciliogenic transcription factorbioRxiv : the preprint server for biology · 2025
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  11. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 5 institutions in 4 countries.

Kiana MohajeriCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
Rachita YadavCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Eva D'haeneCenter for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Philip M BooneCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Serkan ErdinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Dadi GaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Mariana Moyses-OliveiraCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Riya BhavsarCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Benjamin B CurrallCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kathryn O'KeefeCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nicholas D BurtCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Chelsea LowtherCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Diane LucenteCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Monica SalaniCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mathew LarsonCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Claire RedinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Olga DudchenkoThe Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX, USA.
Erez Lieberman AidenThe Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Center for Theoretical Biological Physics and Department of Computer Science, Rice University, Houston, TX, USA; UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA 6009, Australia; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech, Pudong, China.
Björn MentenCenter for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Derek J C TaiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
James F GusellaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Sarah VergultCenter for Medical Genetics, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA. Electronic address: mtalkowski@mgh.harvard.edu.
Broad Institute · USGhent University Hospital · BEMassachusetts General Hospital · USBaylor College of Medicine · USHarvard University · US

Funding

RAPID GENE DISCOVERYP01GM061354 · NIGMS · BRIGHAM AND WOMEN'S HOSPITAL · PI MORTON, CYNTHIA CASSON · 2001 to 2019
$24.3M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
TRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0M
Clinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2M
Assembling the Genetic Architecture of X-linked Dystonia ParkinsonismR01NS102423 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI David Cristopher Bragg, Clotilde Lagier-Tourenne · 2017 to 2026
$5.4M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Functional convergence following disruption of diverse genes associated with neurodevelopmental disordersR01MH123155 · NIMH · YALE UNIVERSITY · PI BRENNAND, KRISTEN JENNIFER, RUDERFER, DOUGLAS · 2021 to 2025
$4.1M
Molecular mechanisms and genetic drivers of reciprocal genomic disordersR01HD096326 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2018 to 2022
$3.5M
Dissecting recurrent microdeletion syndromes using dual-guide genome editingR01NS093200 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI GUSELLA, JAMES F · 2015 to 2019
$2.9M
Defining the Disorders of Genome OrganizationK08NS117891 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI BOONE, PHILIP MICHAEL · 2020 to 2024
$988k
Scalable tools and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR56MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2018 to 2018
$870k
Exploring the genetic architecture of structural birth defectsR03HD099547 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2019 to 2020
$336k
NHGRI NIH HHS U01 HG011755NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD096326NICHD NIH HHS R03 HD099547NIGMS NIH HHS P01 GM061354NIGMS NIH HHS T32 GM007748NIMH NIH HHS R01 MH115957NIMH NIH HHS R01 MH123155NIMH NIH HHS R56 MH115957NINDS NIH HHS K08 NS117891NINDS NIH HHS R01 NS093200NINDS NIH HHS R01 NS102423
6 · The paper itself

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.

Indexed as

Induced Pluripotent Stem CellsNeural Stem CellsGenomeHaploinsufficiencyHumansMEF2 Transcription FactorsNeuronsTranscription, GeneticMEF2C protein, humanMEF2 Transcription FactorschromatinCRISPRgenomicsinduced neuronsiPSCMEF2Cneurodevelopmental disordersTADtopological associating domaintranscriptional regulation

Identifiers

PMID36283406
PMCPMC9674968
OpenAlexW4307295731

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.