Transcription factor 4 (TCF4) is a critical regulator of neurodevelopment and has been linked to the pathogenesis of autism, intellectual disability, and schizophrenia. As a class I bHLH transcription factor it is assumed that TCF4 exerts its neurodevelopmental functions through dimerization with proneural class II bHLH TFs. Here, we aim to identify transcription factor (TF) partners of TCF4 in the control of interhemispheric connectivity formation. Using a new bioinformatic strategy integrating TF expression levels and regulon activities from single cell RNA-sequencing data, we find evidence that TCF4 interacts with non-bHLH TFs and modulates their transcriptional activity in Satb2+ intercortical projection neurons. Notably, this network comprises regulators linked to the pathogenesis of neurodevelopmental disorders, e.g. FOXG1, SOX11 and BRG1. In support of the functional interaction of TCF4 with non-bHLH TFs we find that TCF4 and SOX11 biochemically interact and cooperatively control commissure formation in vivo, and regulate the transcription of genes implied in this process. Next to identifying new candidate interactors of TCF4 in neurodevelopment, this study illustrates how scRNA-Seq data can be leveraged to predict TFs networks in neurodevelopmental processes.
scRNA-Sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development
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Marie-Theres Wittmann, Sayako Katada, Elisabeth Sock, Philipp Kirchner, Arif B. Ekici, Michael Wegner, Kinichi Nakashima, D. Chichung Lie, André Reis; scRNA-Sequencing uncovers a TCF4-dependent transcription factor network regulating commissure development. Development 2021; dev.196022. doi: https://doi.org/10.1242/dev.196022
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