Nuclear phosphoinositide regulation of chromatin

Abstract

Phospholipid signaling has clear connections to a wide array of cellular processes, particularly in gene expression and in controlling the chromatin biology of cells. However, most of the work elucidating how phospholipid signaling pathways contribute to cellular physiology have studied cytoplasmic membranes, while relatively little attention has been paid to the role of phospholipid signaling in the nucleus. Recent work from several labs has shown that nuclear phospholipid signaling can have important roles that are specific to this cellular compartment. This review focuses on the nuclear phospholipid functions and the activities of phospholipid signaling enzymes that regulate metazoan chromatin and gene expression. In particular, we highlight the roles that nuclear phosphoinositides play in several nuclear-driven physiological processes, such as differentiation, proliferation, and gene expression. Taken together, the recent discovery of several specifically nuclear phospholipid functions could have dramatic impact on our understanding of the fundamental mechanisms that enable tight control of cellular physiology.

Keywords: chromatin; gene expression; nuclear phospholipid signaling; phosphoinositides.

FIGURE 1

Lipids play key regulatory roles within the nucleus. Within membranes lipids (a) initiate signal cascades via recruitment of nuclear membrane proteins, as is the case in the best understood pathways correlated with extracellular signaling such as hormonal, cell migration signaling, inflammation or apoptotic response, and intracellular metabolic pathways such as the mTOR pathway; (b) as activators of nuclear receptors that activate or repress transcription, as is the case in PPAR-associated transcription and SF-1 targeted expression; and (c) within enigmatic nuclear micro-structures, such as nuclear speckles, where phospholipids mediate mRNA splicing factor activity (SF), polyadenylating polymerase activity (PAP) and modifications such as mRNA capping (CE). All these important activities highlight the importance of nuclear phospholipids in cellular physiology

FIGURE 2

Possible mechanisms describing how phospholipids reach soluble nuclear receptors. (a) FABP5 is a well-studied shuttle protein that transfers yet unknown lipid ligands to its target nuclear receptor, PPAR, which plays an important role in differentiation, development and metabolism. (b) It is still unknown whether such nuclear receptors as SF-1 retrieve lipid ligands from the inner leaflet of the nuclear membrane and then migrate to the surface of chromatin to enact transcriptional changes, or whether the lipid ligand is shuttled to the nuclear receptor by an unknown vector. (c) It is also possible that nuclear receptors bridge chromatin and lipid ligands within intranuclear membranes, as it has been shown that various loci can co-localize at perinuclear locations, possibly by DNA tethering membrane-based proteins

FIGURE 3

Phosphoinositides can be specifically modified while bound to nuclear proteins. IPMK is capable of phosphorylating phosphatidylinositol-4,5-phosphate (PIP2) with excellent enzyme kinetics when PIP2 was seeded within the transcription factor SF-1, but IPMK is a much poorer enzyme acting on PIP2 help within phospholipid micelles, more accurately representing a typical cytoplasmic membrane context

FIGURE 4

Phospholipase C (PLC) isoforms regulate many signaling pathways. Each isoform is involved in proliferation and growth, including up-regulation of expression of cell cycle genes, mediating checkpoints, calcium signaling involved in gene expression and kinase activation, differentiation, DNA damage response genes and other intranuclear pathways involved in apoptotic gene expression

FIGURE 5

IPMK is involved in gene expression. (a) IPMK enhances p300 acetylation of p53, stabilizing the tumor suppressor and thus subsequent p53-targeted gene expression. (b) IPMK product inositol (1,4,5,6) phosphate is necessary for association of histone deacetylase HDAC3 with the SMRT complex resulting in transcriptional repression of proliferation genes at the site of nucleosomes. (c) IPMK has thus far been identified as the only lipid-modifying enzyme that can phosphorylate PIP₂ within a nuclear receptor resulting in transcriptional activation, effects of which appear to be countered by phosphatase PTEN, and critical in the process of development