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

• Published in: Nature neuroscience Vol. 23; no. 3; pp. 375 - 385
• Main Authors: Phan, BaDoi N., Bohlen, Joseph F., Davis, Brittany A., Ye, Zengyou, Chen, Huei-Ying, Mayfield, Brent, Sripathy, Srinidhi Rao, Cerceo Page, Stephanie, Campbell, Morganne N., Smith, Hannah L., Gallop, Danisha, Kim, Hyojin, Thaxton, Courtney L., Simon, Jeremy M., Burke, Emily E., Shin, Joo Heon, Kennedy, Andrew J., Sweatt, J. David, Philpot, Benjamin D., Jaffe, Andrew E., Maher, Brady J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2020; Nature Publishing Group
• Subjects: 101/28; 13/1; 13/106; 13/51; 14/19; 38/77; 38/91; 631/208/191/2018; 631/378/1689/1373; 631/378/1689/2608; 631/378/2571/219; 631/378/2606; 64/60; 9/30; Aging; Animal Genetics and Genomics; Animal models; Animals; Autism; Autism Spectrum Disorder - genetics; Autopsy; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain; Cell Count; Cell culture; Comparative analysis; DNA Fingerprinting; Facies; Gene Expression Regulation; Gene sequencing; Genetic aspects; Genetic transcription; Human chromosome abnormalities; Humans; Hyperventilation - genetics; Intellectual Disability - genetics; Methyl-CpG-Binding Protein 2 - genetics; Mice; Mice, Knockout; Mutation; Myelin; Myelin proteins; Myelin Sheath - genetics; Myelination; Neurobiology; Neurosciences; Oligodendroglia - metabolism; Primary Cell Culture; PTEN Phosphohydrolase - genetics; Ribonucleic acid; RNA; Rodents; Signal Transduction - genetics; Transcription; Transcription Factor 4 - genetics; Transcriptome - genetics; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-019-0578-x

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. The authors identify an impaired myelination signature from the brains of mouse models of Pitt–Hopkins syndrome and show that it is shared in the postmortem brains of people with autism.