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

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.