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Cited by 36Genetics and Neurodevelopmental DisordersWnt/β-catenin signaling in development and cancerSchizophrenia research and treatment

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

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Hennig, Krista M., Fass, Daniel M., Zhao, Wen-Ning, Sheridan, Steven D., Fu, Ting, Erdin, Serkan, Stortchevoi, Alexei, Lucente, Diane +5 more·2017·Complex Psychiatry
DOI 10.1159/000475666PMC PMC5582445
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Abstract

Genetic variation within the transcription factor TCF4 locus can cause the intellectual disability and developmental disorder Pitt-Hopkins syndrome (PTHS), whereas single-nucleotide polymorphisms within noncoding regions are associated with schizophrenia. These genetic findings position TCF4 as a link between transcription and cognition; however, the neurobiology of TCF4 remains poorly understood. Here, we quantitated multiple distinct TCF4 transcript levels in human induced pluripotent stem cell-derived neural progenitors and differentiated neurons, and PTHS patient fibroblasts. We identify two classes of pharmacological treatments that regulate TCF4 expression: WNT pathway activation and inhibition of class I histone deacetylases. In PTHS fibroblasts, both of these perturbations upregulate a subset of TCF4 transcripts. Finally, using chromatin immunoprecipitation sequencing in conjunction with genome-wide transcriptome analysis, we identified TCF4 target genes that may mediate the effect of TCF4 loss on neuroplasticity. Our studies identify new pharmacological assays, tools, and targets for the development of therapeutics for cognitive disorders.

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Authors
Hennig, K. M., Fass, D. M., Zhao, W.-N., Sheridan, S. D., Fu, T., Erdin, S., Stortchevoi, A., Lucente, D., Cody, J. D., Sweetser, D., Gusella, J. F., Talkowski, M. E., & Haggarty, S. J.
Affiliations
  • Harvard University (US)
  • Broad Institute (US)
  • Massachusetts General Hospital (US)
  • The University of Texas at San Antonio Health Science Center (US)
ORCID
Venue
Complex Psychiatry
Publisher
S. Karger AG
Published
2017
Volume
3
Issue
1
Pages
53-71
ISSN
  • 2673-298X (ISSN-L)
  • 2673-3005
DOI
10.1159/000475666
PMC
PMC5582445
OpenAlex
W2734523516
Cited by
36
References
2
Citations by year
2025: 4 · 2024: 14 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 2
FWCI
1.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Complex Psychiatry (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • University of Pittsburgh
  • National Institute of Mental Health (R01MH095088)
  • National Institute of General Medical Sciences (P01GM061354)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
TCF4, Pitt-Hopkins syndrome, schizophrenia, Wnt/β-catenin signaling, histone deacetylase, epigenetic regulation, iPSC-derived neurons, neuroplasticity, cognitive disorders, transcription factor target genes, intellectual disability

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