Cargando…

Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes

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 und...

Descripción completa

Detalles Bibliográficos
Autores principales: Mullegama, Sureni V., Klein, Steven D., Williams, Stephen R., Innis, Jeffrey W., Probst, Frank J., Haldeman-Englert, Chad, Martinez-Agosto, Julian A., Yang, Ying, Tian, Yuchen, Elsea, Sarah H., Ezashi, Toshihiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163803/
https://www.ncbi.nlm.nih.gov/pubmed/34050248
http://dx.doi.org/10.1038/s41598-021-90798-z
_version_ 1783700981918203904
author Mullegama, Sureni V.
Klein, Steven D.
Williams, Stephen R.
Innis, Jeffrey W.
Probst, Frank J.
Haldeman-Englert, Chad
Martinez-Agosto, Julian A.
Yang, Ying
Tian, Yuchen
Elsea, Sarah H.
Ezashi, Toshihiko
author_facet Mullegama, Sureni V.
Klein, Steven D.
Williams, Stephen R.
Innis, Jeffrey W.
Probst, Frank J.
Haldeman-Englert, Chad
Martinez-Agosto, Julian A.
Yang, Ying
Tian, Yuchen
Elsea, Sarah H.
Ezashi, Toshihiko
author_sort Mullegama, Sureni V.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8163803
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-81638032021-06-01 Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes Mullegama, Sureni V. Klein, Steven D. Williams, Stephen R. Innis, Jeffrey W. Probst, Frank J. Haldeman-Englert, Chad Martinez-Agosto, Julian A. Yang, Ying Tian, Yuchen Elsea, Sarah H. Ezashi, Toshihiko Sci Rep Article 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. Nature Publishing Group UK 2021-05-28 /pmc/articles/PMC8163803/ /pubmed/34050248 http://dx.doi.org/10.1038/s41598-021-90798-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mullegama, Sureni V.
Klein, Steven D.
Williams, Stephen R.
Innis, Jeffrey W.
Probst, Frank J.
Haldeman-Englert, Chad
Martinez-Agosto, Julian A.
Yang, Ying
Tian, Yuchen
Elsea, Sarah H.
Ezashi, Toshihiko
Transcriptome analysis of MBD5-associated neurodevelopmental disorder (MAND) neural progenitor cells reveals dysregulation of autism-associated genes
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163803/
https://www.ncbi.nlm.nih.gov/pubmed/34050248
http://dx.doi.org/10.1038/s41598-021-90798-z
work_keys_str_mv AT mullegamasureniv transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT kleinstevend transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT williamsstephenr transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT innisjeffreyw transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT probstfrankj transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT haldemanenglertchad transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT martinezagostojuliana transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT yangying transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT tianyuchen transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT elseasarahh transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes
AT ezashitoshihiko transcriptomeanalysisofmbd5associatedneurodevelopmentaldisordermandneuralprogenitorcellsrevealsdysregulationofautismassociatedgenes