WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4
| Autor: | David A. Sweetser, Michael E. Talkowski, Ting Fu, Wen-Ning Zhao, Daniel M. Fass, James F. Gusella, Alexei Stortchevoi, Serkan Erdin, Stephen J. Haggarty, Diane Lucente, Krista M. Hennig, Steven D. Sheridan, Jannine D. Cody |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Original Paper Wnt signaling pathway General Medicine TCF4 Biology Cell biology Transcriptome 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Catenin Cancer research Histone deacetylase Epigenetics Induced pluripotent stem cell Transcription factor 030217 neurology & neurosurgery |
| Zdroj: | Complex Psychiatry. 3:53-71 |
| ISSN: | 2673-298X 2673-3005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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