A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

Ba Doi N. Phan; Joseph F. Bohlen; Brittany A. Davis; Zengyou Ye; Huei Ying Chen; Brent Mayfield; Srinidhi Rao Sripathy; Stephanie Cerceo Page; Morganne N. Campbell; Hannah L. Smith; Danisha Gallop; Hyojin Kim; Courtney L. Thaxton; Jeremy M. Simon; Emily E. Burke; Joo Heon Shin; Andrew J. Kennedy; J. David Sweatt; Benjamin D. Philpot; Andrew E. Jaffe; Brady J. Maher

doi:10.1038/s41593-019-0578-x

A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

Ba Doi N. Phan, Joseph F. Bohlen, Brittany A. Davis, Zengyou Ye, Huei Ying Chen, Brent Mayfield, Srinidhi Rao Sripathy, Stephanie Cerceo Page, Morganne N. Campbell, Hannah L. Smith, Danisha Gallop, Hyojin Kim, Courtney L. Thaxton, Jeremy M. Simon, Emily E. Burke, Joo Heon Shin, Andrew J. Kennedy, J. David Sweatt, Benjamin D. Philpot, Andrew E. JaffeBrady J. Maher

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14 Scopus citations

Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Pten^m3m4/m3m4 and Mecp2^tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

Original language	English (US)
Pages (from-to)	375-385
Number of pages	11
Journal	Nature neuroscience
Volume	23
Issue number	3
DOIs	https://doi.org/10.1038/s41593-019-0578-x
State	Published - Mar 1 2020

ASJC Scopus subject areas

General Neuroscience

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Phan, B. D. N., Bohlen, J. F., Davis, B. A., Ye, Z., Chen, H. Y., Mayfield, B., Sripathy, S. R., Cerceo Page, S., Campbell, M. N., Smith, H. L., Gallop, D., Kim, H., Thaxton, C. L., Simon, J. M., Burke, E. E., Shin, J. H., Kennedy, A. J., Sweatt, J. D., Philpot, B. D., ... Maher, B. J. (2020). A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder. Nature neuroscience, 23(3), 375-385. https://doi.org/10.1038/s41593-019-0578-x

Phan, BDN, Bohlen, JF, Davis, BA, Ye, Z, Chen, HY, Mayfield, B, Sripathy, SR, Cerceo Page, S, Campbell, MN, Smith, HL, Gallop, D, Kim, H, Thaxton, CL, Simon, JM, Burke, EE, Shin, JH, Kennedy, AJ, Sweatt, JD, Philpot, BD, Jaffe, AE & Maher, BJ 2020, 'A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder', Nature neuroscience, vol. 23, no. 3, pp. 375-385. https://doi.org/10.1038/s41593-019-0578-x

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title = "A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder",

abstract = "Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.",

author = "Phan, {Ba Doi N.} and Bohlen, {Joseph F.} and Davis, {Brittany A.} and Zengyou Ye and Chen, {Huei Ying} and Brent Mayfield and Sripathy, {Srinidhi Rao} and {Cerceo Page}, Stephanie and Campbell, {Morganne N.} and Smith, {Hannah L.} and Danisha Gallop and Hyojin Kim and Thaxton, {Courtney L.} and Simon, {Jeremy M.} and Burke, {Emily E.} and Shin, {Joo Heon} and Kennedy, {Andrew J.} and Sweatt, {J. David} and Philpot, {Benjamin D.} and Jaffe, {Andrew E.} and Maher, {Brady J.}",

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AU - Davis, Brittany A.

AU - Ye, Zengyou

AU - Chen, Huei Ying

AU - Mayfield, Brent

AU - Sripathy, Srinidhi Rao

AU - Cerceo Page, Stephanie

AU - Campbell, Morganne N.

AU - Smith, Hannah L.

AU - Gallop, Danisha

AU - Kim, Hyojin

AU - Thaxton, Courtney L.

AU - Simon, Jeremy M.

AU - Burke, Emily E.

AU - Shin, Joo Heon

AU - Kennedy, Andrew J.

AU - Sweatt, J. David

AU - Philpot, Benjamin D.

AU - Jaffe, Andrew E.

AU - Maher, Brady J.

PY - 2020/3/1

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N2 - Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

AB - Autism spectrum disorder (ASD) is genetically heterogeneous with convergent symptomatology, suggesting common dysregulated pathways. In this study, we analyzed brain transcriptional changes in five mouse models of Pitt–Hopkins syndrome (PTHS), a syndromic form of ASD caused by mutations in the TCF4 gene, but not the TCF7L2 gene. Analyses of differentially expressed genes (DEGs) highlighted oligodendrocyte (OL) dysregulation, which we confirmed in two additional mouse models of syndromic ASD (Ptenm3m4/m3m4 and Mecp2tm1.1Bird). The PTHS mouse models showed cell-autonomous reductions in OL numbers and myelination, functionally confirming OL transcriptional signatures. We also integrated PTHS mouse model DEGs with human idiopathic ASD postmortem brain RNA-sequencing data and found significant enrichment of overlapping DEGs and common myelination-associated pathways. Notably, DEGs from syndromic ASD mouse models and reduced deconvoluted OL numbers distinguished human idiopathic ASD cases from controls across three postmortem brain data sets. These results implicate disruptions in OL biology as a cellular mechanism in ASD pathology.

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A myelin-related transcriptomic profile is shared by Pitt–Hopkins syndrome models and human autism spectrum disorder

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