Psychiatric risk gene transcription factor 4 preferentially regulates cortical interneuron neurogenesis during early brain development

J Biomed Res. 2022 Jul 28;36(4):242-254. doi: 10.7555/JBR.36.20220074.


Genetic variants within or near the transcription factor 4 gene ( TCF4) are robustly implicated in psychiatric disorders including schizophrenia. However, the biological pleiotropy poses considerable obstacles to dissect the potential relationship between TCF4 and those highly heterogeneous diseases. Through integrative transcriptomic analysis, we demonstrated that TCF4 is preferentially expressed in cortical interneurons during early brain development. Therefore, disruptions of interneuron development might be the underlying contribution of TCF4 perturbation to a range of neurodevelopmental disorders. Here, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 on human medial ganglionic eminence-like organoids (hMGEOs) to identify genome-wide TCF4 binding sites, followed by integration of multi-omics data from human fetal brain. We observed preferential expression of the isoform TCF4-B over TCF4-A. De novo motif analysis found that the identified 5916 TCF4 binding sites are significantly enriched for the E-box sequence. The predicted TCF4 targets in general have positively correlated expression levels with TCF4 in the cortical interneurons, and are primarily involved in biological processes related to neurogenesis. Interestingly, we found that TCF4 interacts with non-bHLH proteins such as FOS/JUN, which may underlie the functional specificity of TCF4 in hMGEOs. This study highlights the regulatory role of TCF4 in interneuron development and provides compelling evidence to support the biological rationale linking TCF4 to the developing cortical interneuron and psychiatric disorders.

Keywords: ChIP-seq; cortical interneuron; hMGEOs; neurogenesis; schizophrenia; transcription factor 4.

Grants and funding

This study was funded by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 17KJB180009) to M.L., the Natural Science Foundation of Jiangsu Province (Grant No. BK20171062) to M.L., and the National Natural Science Foundation of China (Grant No. 81701320) to M.L. We appreciate comments from the editor and anonymous reviewers.