Sin Zachary, Kinnear Evan, Doshi Raj, Chatterjee Sujan, Derbel Houssemeddine, Guha Prasun, Liu Qian
Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, NV, USA.
Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, NV, USA; School of Life Sciences, University of Nevada, Las Vegas, NV, USA.
Biochem Biophys Res Commun. 2025 Jun 20;766:151874. doi: 10.1016/j.bbrc.2025.151874. Epub 2025 Apr 22.
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.
肌醇多磷酸多激酶（IPMK）正逐渐成为核功能的关键调节因子。虽然早期在酵母和细胞系中的研究将IPMK与基因表达联系起来，但最近的研究揭示了它通过激活组蛋白去乙酰化酶1/3（HDAC1/3）来调节组蛋白乙酰化的作用。有趣的是，HDAC1/3与DNA甲基转移酶1（DNMT1）相互作用，稳定DNMT1并促进DNA甲基化。作为HDAC1/3激活剂，IPMK可能由此影响DNA甲基化动态。本研究调查了IPMK基因缺失如何影响DNA甲基化，但其激酶活性的作用仍未得到测试。使用长读长牛津纳米孔测序，我们对超过2800万个CpG位点进行了甲基化分析，发现IPMK缺失导致超过22000个差异甲基化区域（DMR）。通过整合受DMR影响的基因和RNA-seq数据，我们发现35个基因在启动子区域的甲基化与基因表达之间呈负相关。通路分析显示，与组织重塑和造血相关的基因受到影响。值得注意的是，MMP14和LIF在IPMK缺失时启动子区域显示出显著的甲基化变化，导致mRNA和蛋白质表达下降。总的来说，本研究确定IPMK是DNA甲基化的新型调节因子。虽然本研究没有调查IPMK激酶活性在调节DNA甲基化中的作用，但未来的研究将确定IPMK对DNA甲基化的影响是由其激酶活性还是由激酶非依赖机制驱动的。
