Building a schizophrenia genetic network: Evidence that Transcription Factor 4 regulates schizophrenia risk genes.

Background: The transcription factor 4 ( TCF4 ) locus is one of the most robust association findings with schizophrenia (SZ). However, little is known about the genes regulated by the encoded transcription factor. Methods: We conduct chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with functional experiments and SZ association findings. Results: We identified 11,322 TCF4 binding sites present in two ChIP-seq experiments. These binding sites implicated a gene set that was significantly enriched in 1) Gene Ontology categories including axon/neuronal development and insulin signaling, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, 3) genes down-regulated in TCF4 siRNA knockdown experiments, 4) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p -5 ). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site ±10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. Conclusions: These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.