New insights into the role and regulation of nuclear PtdIns(4,5)P₂

Abstract

Nuclear polyphosphoinositides (PPIns) are recognised as lipid messengers critical for regulating various cellular functions, notably gene expression. Despite their established importance, the mechanistic details of how nuclear PPIns influence gene transcription and the dynamics of these processes are insufficiently understood. This study delineates the role of PIP5K1A and its enzymatic product, PtdIns(4,5)P2, in the selective regulation of gene expression through histone H3K4 methylation modulation, a histone modification associated with increased gene transcription. Previous research in our laboratory using yeast two-hybrid assays facilitated the discovery of a direct interaction between PIP5K1A and ASH2L, a core component of histone H3K4 methylation complexes. This interaction, also observed between ASH2L and the Drosophila PIP5K homologue Skittles, suggests evolutionary conservation and highlights a crucial biological function. Here, we build on these findings to show that alterations in the expression of PIP5K1A or ASH2L were found to similarly affect the expression of a subset of genes and the levels of H3K4me3 at gene promoters. Biochemical analysis revealed an interaction between ASH2L and PPIns, and the significance of this interaction was underscored by studying cells with ASH2L knockdown reconstituted with a PPIns-binding deficient ASH2L variant. These findings established the essential role of PPIns in the regulation of H3K4 tri-methylation, gene expression, and tumour cell proliferation. Furthermore, this research introduces the nuclear speckle protein SRSF2, identifying it as a novel regulator of nuclear PtdIns(4,5)P2 concentration. This discovery not only highlights a distinct regulatory mechanism for managing nuclear phosphoinositide levels but also sheds light on the sophisticated network of proteins integral to nuclear lipid signalling maintenance. This investigation into the regulatory roles of nuclear PPIns offers profound insights into the molecular underpinnings of gene expression and epigenetic regulation, suggesting potential targets for therapeutic intervention and enhancing our understanding of cellular regulation and disease mechanism.

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