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

作     者：Yuanyuan Wang Liya Liu Mingyan Lin 

作者机构：State Key Laboratory of Reproductive MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of NeurobiologySchool of Basic Medical SciencesNanjing Medical UniversityNanjingJiangsu 211166China 

出 版 物：《The Journal of Biomedical Research》 (生物医学研究杂志（英文版）)

年 卷 期：2022年第36卷第4期

页      面：242-254页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100205[医学-精神病与精神卫生学] 10[医学] 

基　　金：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.,the National Natural Science Foundation of China(Grant No.81701320)to M.L.We appreciate comments from the editor and anonymous reviewers. 

主　　题：transcription factor 4 hMGEOs cortical interneuron ChIP-seq neurogenesis schizophrenia 

摘      要：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.