The oily nucleus- role of phospholipids in genome biology: membrane-directed roles and signaling in the nucleoplasm.

Phospholipids, widely known for their structural role in cellular membranes, are now also recognized to play pivotal roles in signal transduction, metabolism, and cellular homeostasis. However, the nucleus is often overlooked in the context of phospholipid biology. The dynamic abundance and precise management of the turnover of nuclear phospholipids by dedicated kinases, phosphatases, and phospholipases implies specialized functions. Like the cytoplasm, many of these biological roles occur or are initiated within the nuclear membrane. However, several aspects of nuclear phospholipid biology appear to be based in the nucleoplasm and are mediated by dynamic and soluble lipoprotein complexes. In many cases, the exact working spaces and molecular mechanisms of action of nuclear phospholipids are not yet clearly defined, and their physiology is likely underestimated due to technical challenges. Nonetheless, in recent years, the impact of nuclear phospholipids on the structure and function of the genome has been found to be more multifaceted and complex. In this review, we summarize recent insights into the interactions and biological roles of phospholipids with respect to chromatin, gene regulation, and nuclear physiology, and discuss these roles in the context of two broad functional domains - the nuclear membrane and the nucleoplasm. We argue that a more detailed understanding of the molecular working modes of nuclear phospholipids is crucial to enable their full scientific comprehension, especially when the exploration of the biology of nuclear phospholipids and their dysregulation may offer promising avenues for diagnosis and therapeutic interventions for various genome-linked diseases.