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

BaDoi 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

Nat Neurosci. 2020 Mar;23(3):375-385. doi: 10.1038/s41593-019-0578-x. Epub 2020 Feb 3.

Authors

BaDoi N Phan^#^{1

2}, Joseph F Bohlen^#¹, Brittany A Davis¹, Zengyou Ye¹, Huei-Ying Chen¹, Brent Mayfield¹, Srinidhi Rao Sripathy¹, Stephanie Cerceo Page¹, Morganne N Campbell¹, Hannah L Smith¹, Danisha Gallop¹, Hyojin Kim^{3

4}, Courtney L Thaxton^{3

4}, Jeremy M Simon^{3

5

6}, Emily E Burke¹, Joo Heon Shin^{1

7}, Andrew J Kennedy⁸, J David Sweatt⁹, Benjamin D Philpot^{3

4

6}, Andrew E Jaffe^{10

11

12

13

14

15}, Brady J Maher^{16

17

18}

Affiliations

¹ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
² Medical Scientist Training Program, University of Pittsburgh, Pittsburgh, PA, USA.
³ Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.
⁵ Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
⁶ Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, NC, USA.
⁷ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Chemistry and Biochemistry, Bates College, Lewiston, ME, USA.
⁹ Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹⁰ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. [email protected].
¹¹ Department of Mental Health, Johns Hopkinds Bloomberg School of Public Health, Baltimore, MD, USA. [email protected].
¹² Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. [email protected].
¹³ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁴ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁵ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁶ Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. [email protected].
¹⁷ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
¹⁸ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging
Animals
Autism Spectrum Disorder / genetics*
Cell Count
DNA Fingerprinting*
Facies
Gene Expression Regulation
Humans
Hyperventilation / genetics*
Intellectual Disability / genetics*
Methyl-CpG-Binding Protein 2 / genetics
Mice
Mice, Knockout
Myelin Sheath / genetics*
Oligodendroglia / metabolism
PTEN Phosphohydrolase / genetics
Primary Cell Culture
Signal Transduction / genetics
Transcription Factor 4 / genetics
Transcriptome / genetics*

Substances

Mecp2 protein, mouse
Methyl-CpG-Binding Protein 2
Tcf4 protein, mouse
Transcription Factor 4
PTEN Phosphohydrolase
Pten protein, mouse

Supplementary concepts

Pitt-Hopkins syndrome

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding