IPMK depletion influences genome-wide DNA methylation.

Inositol polyphosphate multikinase (IPMK) is emerging as a critical regulator of nuclear functions. While earlier studies in yeast and cell lines linked IPMK to gene expression, recent work reveals its role in modulating histone acetylation through the activation of histone deacetylases 1/3 (HDAC1/3). Interestingly, HDAC1/3 interact with DNA methyltransferase 1 (DNMT1), stabilizing DNMT1 and promoting DNA methylation. As an HDAC1/3 activator, IPMK may thereby influence DNA methylation dynamics. This study investigates how the genetic depletion of IPMK influences DNA methylation, though the role of its kinase activity remains untested. Using long-read Oxford nanopore sequencing, we conducted methylation analysis for >28 millions of CpG sites and discovered that IPMK deletion results in over 22,000 differentially methylated regions (DMRs). Integrating affected genes by DMRs and RNA-seq data, we found that 35 genes show an inverse correlation between methylation in promoter regions and gene expression. Pathway analysis revealed that genes related to tissue remodeling and hematopoiesis are affected. Notably, MMP14 and LIF showed significant methylation changes in promoter regions under IPMK deletion, resulting in decreased mRNA and protein expression. Collectively, this study identifies IPMK as a novel regulator of DNA methylation. While this study did not investigate the role of IPMK's kinase activity in regulating DNA methylation, future studies will determine whether IPMK's effects on DNA methylation are driven by its kinase activity or by kinase-independent mechanisms.