Structural insights into a highly flexible zinc finger module unravel INSM1 function in transcription regulation

Orderly development of neuroendocrine and nervous system of mammals requires INSM1, a key regulator for cell differentiation. Ectopic expression of INSM1 is closely correlated with human neuroendocrine tumorigenesis, which makes INSM1 a reliable diagnostic biomarker and potential therapeutic target. To date, INSM1 is known as a transcription repressor binding to GGGG-contained DNA element and TEAD1 using its five zinc fingers (ZFs), while the binding mechanism remains unknown. Here, we reveal highly variable conformations of the whole structure of the five ZFs, among which ZF1 adopts an unusual CCHC-fold. ZF1 binds to the TEAD domain of TEAD1 through hydrophobic interactions, and forms a ternary complex with TEAD1 and TEAD1-targeted DNA. Based on this, INSM1 cooperates with TEAD1 to repress the transcription of TEAD1-targeted genes. ZF2 and ZF3 of INSM1 can bind to DNA but have no specificity to the GGGG-contained element due to long flexible interdomain linker. Instead, INSM1 collaborates with CTCF to target genome loci having the GGGG-contained element and regulate the expression of adjacent genes. This study defines a functional mode of INSM1 by cooperating with diverse DNA-binding proteins for targeting specific genome loci in transcription regulation, and provides structural information for designing INSM1-related therapeutic drugs and diagnostic probes. INSM1 is a key regulator of neuroendocrine differentiation and a biomarker for tumorigenesis. Here, the authors reveal the dynamic conformations of its five zinc fingers and show how INSM1 cooperates with TEAD1 and CTCF to regulate transcription by targeting specific genomic loci.