Transcriptional regulation by nuclear phosphoinositides

Abstract

Phosphoinositides are a family of seven lipids that are present in various subcellular compartments at low levels, compared to other phospholipids. Their levels are regulated by an array of kinases and phosphatases that respond to extrinsic and intrinsic signals in order to change the phosphoinositide profile in different compartments. For example in the nucleus the phosphoinositide PtdIns5P is phosphorylated by the lipid kinase PIP4K2B to generate PtdIns(4,5)P2. In response to activation of stress pathways, PIP4K2B becomes phosphorylated and less active and this in part leads to an increase in nuclear PtdIns5P. Changes in nuclear PtdIns5P are sensed by nuclear proteins that contain lipid interaction motifs which act to transduce the changes in the level of nuclear PI into changes in functional output. PIP4K2B is present in muscle tissue and in myoblasts and we have investigated how its expression regulates myogenic differentiation. Using C2C12 cells as a model of myogenesis we have identified a pathway that illustrates how signalling through PIP4K2B/PtdIns5P can directly regulate gene transcription. Further characterisation of nuclear proteins that can interact with phosphoinositides suggest that changes in nuclear PI are likely to impact on many aspect of chromatin regulation and eventually on transcriptional output.