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

Krista M Hennig; Daniel M Fass; Wen-Ning Zhao; Steven D Sheridan; Ting Fu; Serkan Erdin; Alexei Stortchevoi; Diane Lucente; Jannine D Cody; David Sweetser; James F Gusella; Michael E Talkowski; Stephen J Haggarty

doi:10.1159/000475666

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

Mol Neuropsychiatry. 2017 Jul;3(1):53-71. doi: 10.1159/000475666. Epub 2017 Jul 14.

Authors

Krista M Hennig^{1

2

3}, Daniel M Fass^{1

2

3

4}, Wen-Ning Zhao^{1

2

3}, Steven D Sheridan^{1

2

3}, Ting Fu^{1

2

3}, Serkan Erdin^{5

6}, Alexei Stortchevoi^{5

6}, Diane Lucente^{5

6}, Jannine D Cody^{7

8}, David Sweetser^{6

9}, James F Gusella^{5

6

10}, Michael E Talkowski^{2

5

6}, Stephen J Haggarty^{1

2

3

4

5

6}

Affiliations

¹ Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts, USA.
² Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
³ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts, USA.
⁵ Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Chromosome 18 Clinical Research Center, Department of Pediatrics, University of Texas Health Sciences Center, San Antonio, Texas, USA.
⁸ The Chromosome 18 Registry and Research Society, San Antonio, Texas, USA.
⁹ Divisions of Pediatric Hematology/Oncology and Medical Genetics, Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

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.

Keywords: Drug discovery; Epigenetics; Histone deacetylase; Pitt-Hopkins syndrome; Schizophrenia; TCF4; WNT.

Abstract

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