Transcriptional regulation of schizophrenia risk gene TCF4 in inhibitory neurons during neurodevelopment

The pathology underlying schizophrenia (SCZ) involves cell type-specific and developmental stage-specific dysregulation of multiple gene regulatory networks dominated by some key transcription factors, such as SCZ risk gene transcription factor 4 (TCF4). Previous studies on the regulatory mechanism of TCF4 use SY5Y as the cellular model, which could not reflect its cell typespecific role in the real world. Using the transcriptional profile of whole brain during development stages and single-cell transcriptome data in the developing human prefrontal cortex, we found that TCF4 was preferentially expressed in the interneuron. Chromatin immunoprecipitation combined with sequencing (ChIP-Seq) in human embryonic stem cells (hESC)-derived interneurons revealed that TCF4 primarily activate transcription of genes associated with cortex development and telencephalon regionalization in a long-range manner. As expected, the downstream targets of TCF4 were distinct in inhibitory neurons and neural stem cells during early neurodevelopment, justifying the importance of our study. Deeper investigation further revealed that TCF4 regulate genes related to neurotransmission distally in interneuron in a c-FOS dependent manner, while TCF4 and TCF3 synergistically regulate genes associated with cell proliferation associated proximally in neural stem cells. Our findings suggested that defects in development of interneuron, for instance as a result of TCF4 abnormality, may break excitation and inhibition balance and contribute significantly to the risk of SCZ.