Characterization of a role of inositol polyphosphate multikinase in the regulation of SWI/SNF complex-mediated transcription

Abstract

Inositol polyphosphates are a class of signaling messengers that modulate crucial cellular functions. IPMK, an essential enzyme for the production of inositol polyphosphates IP4 and IP5, is also involved in gene expression regulation. In yeasts, IP4, IP5, and IP6 affect the activity of chromatin remodeling complexes, which play a critical role in gene expression by regulating chromatin accessibility. However, the direct linkage between IPMK and chromatin-related factors remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. My study was the first to demonstrate the direct interaction between IPMK and core subunits of the SWI/SNF complex, including SMARCB1 and BRG1. Moreover, the specific domains required for the IPMK-SMARCB1 binding were determined, and I discovered a functional linkage between IPMK andSMARCB1 by identifying specific genes that are regulated by these proteins via genome-wide analyses. Moreover,I observed that IPMK, SMARCB1, and BRG1 were co-localized at the chromatin, particularly at the promoter-TSS region. Finally, I found that IPMK at least partially regulated the localization of BRG1 at the promoter-TSS region of specific genes. These findings suggest that IPMK plays an important role in promoter targeting of the SWI/SNF complex, thereby contributing to SWI/SNF-meditated transcription.