Abstract
Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-β signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes.
Highlights
Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor involved in neurodevelopment and dendritic cell diversification in the immune system [1,2,3,4,5]
To determine the effects of TCF4 depletion on gene expression in a cell line of neuronal origin, we tested a series of small interfering RNA (siRNA) duplexes for their efficacy in knocking down TCF4 in SH-SY5Y cells
SH-SY5Y cells were chosen because they express high levels of TCF4 and can be efficiently transfected with single siRNA duplexes to achieve a robust knockdown
Summary
Transcription factor 4 (TCF4) is a basic helix-loop-helix (bHLH) transcription factor involved in neurodevelopment and dendritic cell diversification in the immune system [1,2,3,4,5]. Mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS); a severe mental retardation syndrome associated with a facial gestalt, breathing abnormalities, visual problems, delayed speech development and seizures [6,7,8]. PTHS is caused by deletions, nonsense and missense mutations in the TCF4 gene on human chromosome 18, resulting in haploinsufficiency [6,7,8,9]. The majority of TCF4 missense mutations cluster in the bHLH domain of the protein where they attenuate transcription and can impair protein–protein interactions [6,8,10,11,12]. In addition to PTHS, balanced chromosomal abnormalities disrupting TCF4 and copy number variants have been found in patients with autism and neurodevelopmental disorders that were previously undiagnosed with PTHS [13]
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