Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes
Abstract MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains la...
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2021-05-01
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Online Access: | https://doi.org/10.1038/s41598-021-90798-z |
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doaj-e6d18d28ad8c4705b934f15392ca5b202021-05-30T11:33:56ZengNature Publishing GroupScientific Reports2045-23222021-05-0111111210.1038/s41598-021-90798-zTranscriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genesSureni V. Mullegama0Steven D. Klein1Stephen R. Williams2Jeffrey W. Innis3Frank J. Probst4Chad Haldeman-Englert5Julian A. Martinez-Agosto6Ying Yang7Yuchen Tian8Sarah H. Elsea9Toshihiko Ezashi10Department of Molecular and Human Genetics, Baylor College of MedicineDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles10X GenomicsDepartments of Human Genetics, Pediatrics and Internal Medicine, University of MichiganDepartment of Molecular and Human Genetics, Baylor College of MedicineMission Fullerton Genetics CenterDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los AngelesDepartment of Molecular Pharmacology and Physiology, University of South FloridaDivision of Animal Sciences and Bond Life Sciences Center, University of MissouriDepartment of Molecular and Human Genetics, Baylor College of MedicineDivision of Animal Sciences and Bond Life Sciences Center, University of MissouriAbstract MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states.https://doi.org/10.1038/s41598-021-90798-z |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sureni V. Mullegama Steven D. Klein Stephen R. Williams Jeffrey W. Innis Frank J. Probst Chad Haldeman-Englert Julian A. Martinez-Agosto Ying Yang Yuchen Tian Sarah H. Elsea Toshihiko Ezashi |
spellingShingle |
Sureni V. Mullegama Steven D. Klein Stephen R. Williams Jeffrey W. Innis Frank J. Probst Chad Haldeman-Englert Julian A. Martinez-Agosto Ying Yang Yuchen Tian Sarah H. Elsea Toshihiko Ezashi Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes Scientific Reports |
author_facet |
Sureni V. Mullegama Steven D. Klein Stephen R. Williams Jeffrey W. Innis Frank J. Probst Chad Haldeman-Englert Julian A. Martinez-Agosto Ying Yang Yuchen Tian Sarah H. Elsea Toshihiko Ezashi |
author_sort |
Sureni V. Mullegama |
title |
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes |
title_short |
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes |
title_full |
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes |
title_fullStr |
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes |
title_full_unstemmed |
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes |
title_sort |
transcriptome analysis of mbd5-associated neurodevelopmental disorder (mand) neural progenitor cells reveals dysregulation of autism-associated genes |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-05-01 |
description |
Abstract MBD5-associated neurodevelopmental disorder (MAND) is an autism spectrum disorder (ASD) characterized by intellectual disability, motor delay, speech impairment and behavioral problems; however, the biological role of methyl-CpG-binding domain 5, MBD5, in neurodevelopment and ASD remains largely undefined. Hence, we created neural progenitor cells (NPC) derived from individuals with chromosome 2q23.1 deletion and conducted RNA-seq to identify differentially expressed genes (DEGs) and the biological processes and pathways altered in MAND. Primary skin fibroblasts from three unrelated individuals with MAND and four unrelated controls were converted into induced pluripotent stem cell (iPSC) lines, followed by directed differentiation of iPSC to NPC. Transcriptome analysis of MAND NPC revealed 468 DEGs (q < 0.05), including 20 ASD-associated genes. Comparison of DEGs in MAND with SFARI syndromic autism genes revealed a striking significant overlap in biological processes commonly altered in neurodevelopmental phenotypes, with TGFβ, Hippo signaling, DNA replication, and cell cycle among the top enriched pathways. Overall, these transcriptome deviations provide potential connections to the overlapping neurocognitive and neuropsychiatric phenotypes associated with key high-risk ASD genes, including chromatin modifiers and epigenetic modulators, that play significant roles in these disease states. |
url |
https://doi.org/10.1038/s41598-021-90798-z |
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