IPMK physically binds to the SWI/SNF complex and modulates BRG1 occupancy

Inositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin-remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screening approaches and in vivo/in vitro immunoprecipitations, here we demonstrated that mammalian IPMK physically interacts with the SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using the CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate the expression of a common gene set, validating a functional link between IPMK and the SWI/SNF complex. Together, these findings show that IPMK regulates promoter-targeting of the SWI/SNF complex and thereby contributes to SWI/SNF-meditated chromatin accessibility, transcription, and differentiation. Overall design: For RNA-seq experiment: Strand-specific mRNA-Seq of Control (EgfpKD) and IpmkKD in mouse embryonic stem cells (mESCs) and mouse embryonic fibroblasts (MEFs). For ATAC-seq experiment: Genome-wide analysis of chromatin accessibility upon IPMK depletion in mESCs. For CUT&RUN experiment: Genome-wide distributions of BRG1 upon IPMK depletion (siRNA-mediated and shRNA-mediated) in mESCs.