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Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons / Catarina M. SEABRA in Molecular Autism, 11 (2020)
[article]
Titre : Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur Article en page(s) : 45 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 45 p.[article] Transcriptional consequences of MBD5 disruption in mouse brain and CRISPR-derived neurons [Texte imprimé et/ou numérique] / Catarina M. SEABRA, Auteur ; Tatsiana ANEICHYK, Auteur ; Serkan ERDIN, Auteur ; Derek J. C. TAI, Auteur ; Celine E. F. DE ESCH, Auteur ; Parisa RAZAZ, Auteur ; Yu AN, Auteur ; Poornima MANAVALAN, Auteur ; Ashok RAGAVENDRAN, Auteur ; Alexei STORTCHEVOI, Auteur ; Clemer ABAD, Auteur ; Juan I. YOUNG, Auteur ; Patricia MACIEL, Auteur ; Michael E. TALKOWSKI, Auteur ; James F. GUSELLA, Auteur . - 45 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 45 p.
Mots-clés : Autism spectrum disorder Crispr Mbd5 Mouse Ndd Neurons Transcriptomics Index. décimale : PER Périodiques Résumé : BACKGROUND: MBD5, encoding the methyl-CpG-binding domain 5 protein, has been proposed as a necessary and sufficient driver of the 2q23.1 microdeletion syndrome. De novo missense and protein-truncating variants from exome sequencing studies have directly implicated MBD5 in the etiology of autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs). However, little is known concerning the specific function(s) of MBD5. METHODS: To gain insight into the complex interactions associated with alteration of MBD5 in individuals with ASD and related NDDs, we explored the transcriptional landscape of MBD5 haploinsufficiency across multiple mouse brain regions of a heterozygous hypomorphic Mbd5(+/GT) mouse model, and compared these results to CRISPR-mediated mutations of MBD5 in human iPSC-derived neuronal models. RESULTS: Gene expression analyses across three brain regions from Mbd5(+/GT) mice showed subtle transcriptional changes, with cortex displaying the most widespread changes following Mbd5 reduction, indicating context-dependent effects. Comparison with MBD5 reduction in human neuronal cells reinforced the context-dependence of gene expression changes due to MBD5 deficiency. Gene co-expression network analyses revealed gene clusters that were associated with reduced MBD5 expression and enriched for terms related to ciliary function. LIMITATIONS: These analyses included a limited number of mouse brain regions and neuronal models, and the effects of the gene knockdown are subtle. As such, these results will not reflect the full extent of MBD5 disruption across human brain regions during early neurodevelopment in ASD, or capture the diverse spectrum of cell-type-specific changes associated with MBD5 alterations. CONCLUSIONS: Our study points to modest and context-dependent transcriptional consequences of Mbd5 disruption in the brain. It also suggests a possible link between MBD5 and perturbations in ciliary function, which is an established pathogenic mechanism in developmental disorders and syndromes. En ligne : http://dx.doi.org/10.1186/s13229-020-00354-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies / Andre W. PHILLIPS ; Elena ARTIMOVICH ; Jonathan E. NESTOR ; John P. HUSSMAN ; Gene J. BLATT in Autism Research, 9-5 (May 2016)
[article]
Titre : Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies Type de document : Texte imprimé et/ou numérique Auteurs : Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur Article en page(s) : p.513-535 Langues : Anglais (eng) Mots-clés : human stem cells autism drug-screening high-throughput inducible pluripotent stem cells CRISPR optogenetics organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289
in Autism Research > 9-5 (May 2016) . - p.513-535[article] Human Inducible Pluripotent Stem Cells and Autism Spectrum Disorder: Emerging Technologies [Texte imprimé et/ou numérique] / Andre W. PHILLIPS, Auteur ; Elena ARTIMOVICH, Auteur ; Jonathan E. NESTOR, Auteur ; John P. HUSSMAN, Auteur ; Gene J. BLATT, Auteur . - p.513-535.
Langues : Anglais (eng)
in Autism Research > 9-5 (May 2016) . - p.513-535
Mots-clés : human stem cells autism drug-screening high-throughput inducible pluripotent stem cells CRISPR optogenetics organoids Index. décimale : PER Périodiques Résumé : Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. En ligne : http://dx.doi.org/10.1002/aur.1570 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=289