Lipid–Nucleic Acid Interactions: Shaping Genetic Information

Credit: Janélie Bêcle Nucleic acids, proteins, carbohydrates, and lipids are the four major biomolecules constituting living organisms. Cellular processes are mediated by the concerted action of these biomolecules, thus giving rise to complex interaction networks and signaling pathways. Yet, although two-thirds of the cell proteome is documented to be in constant interaction with multiple lipid species (Li et al. 2010), there is a poor definition of the prevalence and the importance of lipid–nucleic acid interactions. Only scattered evidence provides, at present, connections, either direct or indirect, between lipids and RNA, DNA, or chromatin. Yet, if better understood, this would improve our view of how the genetic information encoded in nucleic acids could be preserved, modified, or revealed. It is therefore necessary to gather, federate, and connect as much new knowledge as we can regarding lipid–nucleic acid interactions to ensure that the current gap of knowledge does not condition our informed understanding of biological processes. In this thematic collection, four updated reviews and five original research articles shape the state of the art of this young field, and showcase how important it is to invest efforts on developing it further. The disequilibrium underlying why lipid–nucleic acid interactions have been so poorly explored in comparison to protein–nucleic acid ones relates to historical reasons (reviewed in Samardak et al. 2024) but also to the difficulty of applying classical lipid-related techniques to a nucleic-acid-rich territory as a nucleus (reviewed in Moriel-Carretero 2021). In this collection, Sayed et al. (2025) make a comprehensive analysis of the experimental methods applied in, or applicable to, lipid–chromatin research, including biophysical, structural, and cell biology approaches, with a critical assessment of their strengths and weaknesses. Their exploration culminates with two important messages, namely that nuclear lipids exert a widespread impact on chromatin that is underestimated at present, and that, as anticipated, this lack of realization is mostly to be ascribed to experimental challenges. Their complete overview of the technological limitations and possibilities provides an exceptional resource to break this detrimental dynamic. An important consideration to dive into how lipids may shape genetic information stems from the natural connection, within the cell, of multiple biosynthetic pathways, within which molecules do commit for one out of different possible routes. In this sense, the inability of membrane phospholipids to accept methyl groups during the synthesis of phosphatidylcholine was shown to lead to increased histone methylation. In becoming acceptors, methylated histones altered the epigenetic landscape, thus genetic information usage (Ye et al. 2017). Another interesting example relates to nucleoside triphosphates (NTPs), given that they fulfill multiple roles beyond nucleic acid synthesis: ATP, as the primary energy brick, nourishes numerous biological processes via phosphate bond hydrolysis; GTP acts in signal transduction; UTP acts as a phosphate donor in sugar metabolism, being crucial for glycosylation; and both ATP and CTP are involved in lipid metabolism, where ATP donates phosphate groups to phosphorylate choline and ethanolamine and CTP carries energy for head group attachment (reviewed by Qiu and Ye 2025). A recent study using the eukaryotic model organism Saccharomyces cerevisiae showed that the attenuation of the Kennedy pathway, which results in lower phospholipid production, elevates pyrimidine nucleotides like CMP (Zhu et al. 2025). This de novo nucleotide synthesis, relying on the pentose phosphate pathway, increases the production of the reducing coenzyme NADPH, which in turn enhances glutathione synthesis (Zhu et al. 2025). Beyond implications for management of oxidative stress, the increased availability in nucleotides very likely has a yet-to-be-explored impact on RNA synthesis levels, RNA polymerases’ transcriptional kinetics and, as a by-product, an impact on genome expression and coordination with other DNA-based processes. In this collection, Qiu and Ye (2025) explore the recent advances in understanding the functional roles of glycerophospholipid biosynthesis beyond their structural functions, gather, connect, and analyze the current knowledge, overall proposing that glycerophospholipid biosynthesis plays an integrative role in metabolic regulation. Phosphoinositides (PPIns) are a type of phospholipids whose polar head consists of an inositol ring whose phosphorylation at positions 3, 4, and/or 5 gives rise to seven possible variants. Beyond well-characterized cytoplasmic distribution and function (reviewed in Posor et al. 2022), PPIns are present in the nucleus, and their levels are responsive to multiple stimuli, suggesting since several decades now their potential role in regulating specific nuclear functions (reviewed in Olazabal-Morán et al. 2020). Isolation of PPIns-binding proteins from intact nuclei revealed an overrepresentation of factors related to RNA splicing, chromatin assembly, and DNA topology (Lewis et al. 2011), and subsequent characterization of some of these hits revealed a nucleating role of PPIns during the conformation of membrane-less organelles such as the nucleolus (Karlsson et al. 2016). This is worth considering more seriously, since recent unbiased metabolic characterization of different cellular condensates discovered that, along with RNA, phospholipids provide a scaffolding role ensuring functional liquid–liquid phase separation (Dumelie et al. 2024). In this collection, Hifdi et al. (2025) revisit the evidence regarding the functions of PPIns in the cytoplasm, as well as that pointing at the nucleus, and make emerge an irrefutable impact of PPIns in transcription and chromatin regulation. Both through the description of past and current progress, they showcase key discoveries on how PPIns modulate nuclear factors activity, thus impacting chromatin to modify gene expression, and provide a holistic view of how nuclear and cytosolic PPIns branches coordinate in orchestrating transduction cascades crucial for cell physiology. Lipid droplets (LD) are dynamic organelles born from the endoplasmic reticulum harboring a neutral lipid core surrounded by a phospholipid monolayer onto which proteins assemble, either directly, or by lipidation moieties or via stably anchored partners. They store lipids to build reserves, to detoxify the cell from a lipid excess, or to protect lipids at risk from harm, such as oxidative damage (reviewed in Moriel-Carretero 2021). Also, the proteome decorating LD is evolving and adapts to cellular needs, being responsive to the type of lipids stored in its core (Fei et al. 2011). This makes of LD surface a platform able either to titrate proteins from elsewhere in the cell or to selectively gather them to create functional outputs. In this respect, LD recruit transcription factors, such as MLX in human cells, MLDSR in bacteria, and Opi1 in budding yeast (reviewed in Moriel-Carretero 2021). Moreover, LD are reported to bind nucleic acids, in particular RNA (Dvorak et al. 2003), and can provide metabolites to adjacent structures, such as fatty acid supply to acetylate chromatin (Umaru et al. 2023), altogether making emerge the possibility of transcriptional regulatory networks. Yet, in eukaryotic cells, LD can be found both in the cytoplasm and in the nucleus (reviewed in Samardak et al. 2024), the mentioned transcription factors can shuttle between these two compartments and, as such, dissecting the potential coordination of transcriptional programs by LD is difficult. A compelling way of uncovering this link therefore stems from prokaryotic systems, where the lack of a nuclear envelope (NE) allows all the components of the system (LD, genomic DNA, and transcriptional machineries) to coexist in time and space. This is the strategy undertaken by Alvarez et al. (2025) in this special collection, where they convincingly draw a complex tripartite regulatory circuit featured by oleaginous bacteria: by competing for a transcriptional factor (which impacts its dimerization potential), LD and DNA dictate transcriptional outputs that, among others, regulate the lipogenesis status of the cells, thus signaling back on LD content, size, and titrating potential. The functional impact of this regulation goes beyond gene expression programs, also conditioning genome protection against environmental stresses. Thus, the panorama sculpted by Alvarez et al. allows to visualize, in a minimalistic manner, the true nature of LD as transcriptional network regulators. On top of the above considerations regarding the regulation of RNA expression by LD, the interaction of RNA with membranes is also worth exploring. This interaction underlies the basis of the replication of multiple RNA viruses (Roingeard et al. 2022), the transport of messenger RNAs toward unique subcellular destinations where the encoded protein is to be specifically translated (Jansen et al. 2014), and the loading of RNAs within exosomes that will be secreted, sending information elsewhere in the organism (Janas et al. 2020). Beyond acting as a carrier of information, RNA can fold into ribozymes with catalytic function, and it was previously reported that lipid within membranes can directly interact with an artificial ribozyme, changing its activity (Czerniak and Saenz 2022). However, the potential effect of lipids on naturally occurring ribozymes had remained unexplored. In this collection, Czerniak and Saenz (2025) show that both the catalytic activity and the RNA integrity of natural ribozymes can be controlled by different membrane properties, which include its gel/liquid status. This implies that different combinations of ribozyme and membrane composition will yield different activity outcomes, widening the horizon of how we envision the regulation of ribozyme function in cells, during pathogenesis, and during evolution. An ineludible aspect of lipid–nucleic acid interactions relates to the function and integrity of the NE, which encloses the nuclear genome, structurally and functionally defining the nucleus. The NE is formed by the outer nuclear membrane, which is in continuity with the membrane of the endoplasmic reticulum; the inner nuclear membrane, which faces the nucleoplasm; and the regions with extreme curvature where both membranes meet, scaffolded by the nuclear pore complexes, which allow exchanges between the confined nuclear space and the rest of the cell. Biochemical analyses of the NE revealed approximately 0.33 mg of lipids per 1 mg of proteins, thus indicating that the lipid fraction, on average, represents 30% of total NE mass. Of this, glycerophospholipids and cholesterol species appeared as the main components (reviewed in Samardak et al. 2024). Other important species belong to the sphingolipid family (and its precursors) despite being present in low amount: first, ceramides are important in the nuclear pore complex vicinity (Cheng et al. 2019), presumably because, being long molecules, they assist the dramatic bending of the membrane at this location; second, sphingolipids and its precursors are crucial in warranting NE homeostasis, genome integrity, and resistance to aneuploidy (Hwang et al. 2017; Hwang et al. 2025; Hwang et al. 2019). On a functional note, however, we are at our infancy in understanding how the lipid composition of the NE defines, or even rules, genome behavior and stability (reviewed in Bâcle et al. 2023). An interesting start point is provided by inner nuclear membrane-anchored proteins that attach chromatin to the periphery. For example, chromatin–envelope interactions mediated by condensins are sufficient to instruct compaction forces that end up in NE invaginations toward the nucleoplasmic space (Bozler et al. 2015). In this collection, Bosch-Calvet et al. (2025) extend this concept toward a massive NE reorganization: the formation of toroidal nuclei. These doughnut-shaped nuclei can emerge after cell passage through mitosis and are a hallmark of chromosome segregation defects, first described when cells experience defective autophagy (Almacellas et al. 2021). The toroidal nucleus thus represents an informative marker of chromosomal instability with predictive value that complements the classically used assessment of micronuclei formation frequency. Bosch-Calvet et al. (2025) demonstrate that the incidence of toroidal nuclei formation decreases as chromatin loosens and NE stiffness decreases. The latter is brought about by playing with lamin levels and nourishes the idea that the crosstalk between chromatin and membranes can be attenuated by the scaffolding function of the lamina in the organisms that possess it (Bozler et al. 2015; Sołtysik et al. 2019). This raises the question of how, in the absence of lamina, the chromatin–membrane interactions are handled. This is the case of the model yeast S. cerevisiae and, in this collection, Rodríguez-Herrera and colleagues tackle this problem. They create an inducible, degradable version of Nem1, part of a phosphatase complex that controls NE membrane biogenesis. This way, Nem1 depletion provokes an excess of membrane that leads to abnormal NE evaginations in interphase that, the authors show, provoke aberrant chromatin protrusions that persist into mitosis. Importantly, this results in lagging chromatin during late anaphase, overall illustrating that the NE membrane is crucial for timely chromosome segregation, inaccuracy of which has a negative impact on subsequent cell cycles (Rodríguez-Herrera et al. 2025). Last, it is worth asking if the reciprocal is also true, namely if membranes are sensitive to alterations in their interaction with chromatin. In this collection, Sosa Ponce et al. (2025) report that removing or mutating the chromatin-binding, inner nuclear membrane-resident proteins Sir4, Esc1, or Mps3 dispatch sterols away from the NE. This powerful notion raises the possibility that a structuration of sterol domains exists under given chromatin conformations that, if altered due to changes in its mobility, anchoring, or compaction, can lead to a remodeling of sterol metabolism. A last aspect of lipid–nucleic acid interactions concerns the possibility that lipid moieties may condition DNA integrity preservation. This can happen indirectly. For example, the master kinases of the DNA damage response (DDR), ATR and ATM, react to harmed DNA to launch and organize its subsequent repair. They belong to the family of phosphatidyl-inositol-3-kinase-related kinases (PIKKs), which are thought not to bear the ability to phosphorylate phosphatidylinositol (PI) moieties any longer (Hunter 1995), yet may have kept their ability to interact with such molecules. It was recently demonstrated that ATM binding to the pool of the lipid PI4P present within Golgi membrane allows to dose its presence within the nucleus, thus finetuning the kinetics and intensity of the DDR (Ovejero et al. 2023). Regarding the other DDR kinase, ATR, it can bind cellular membranes in several instances. These include the outer mitochondrial membrane upon nutrient shortage (Yi et al. 2017); the NE upon nuclear swelling caused by hyper-osmotic stress (Kumar et al. 2014); responding to an increase in membrane fluidity upon excess of polyunsaturated fatty acids (Zhang et al. 2007); and monitoring timely membrane scission at the cytokinesis site, where constriction is highest (Luessing et al. 2022). The common denominator of these situations is the presence, within membranes, of membrane packing defects, that is, regions of the membrane where the polar heads of the composing phospholipids split apart, thus exposing the internal apolar moieties. This suggests that membrane packing defects may stimulate ATR's activity, and indeed a coordination exists between the type and quantity of nuclear phospholipids and the cell's ability to sense damaged DNA (Ovejero et al. 2022), implying that an ability of ATR to probe membranes may synergize with its capacity to detect and signal damaged DNA. An alternative (and not exclusive) contribution of lipid–nucleic acid interactions to DNA integrity preservation could stem from a direct contact between both types of molecules. In this collection, Soulet et al. (2025) report that neutral lipids can stabilize DNA, likely through the interaction of triacylglycerols with the DNA bases (Zhdanov et al. 2015; Zhdanov et al. 2002). This work found that genomic DNA fragments subjected to an electrophoretic field migrate less when intermingled with neutral lipids than in their absence, and this irrespective of whether delipidation was applied in vitro, using acetone, or in vivo, by subjecting cells to serum deprivation (Soulet et al. 2025). In cells, neutral lipids, of an apolar nature, accumulate in the core of LD or are sandwiched between the two leaflets of a membrane, thus being exposed by membrane packing defects. The new frame provided by Soulet et al. raises a synergic scenario whereby membrane packing defects, which seem to attract ATR, may help increase its residence time and signaling power within the nucleus by a simultaneous neutral lipid-mediated retention of DNA and restriction of its mobility. In sum, this is a timely and pertinent collection that broadens our understanding of an emerging field. In the following, we will perhaps discover that lipids instruct RNA post-transcriptional modifications dictating RNA splicing, stability, nuclear export polarity, or translation frequency. It could also be that specific NE lipid profiles determine the type of repair undergone by a broken DNA molecule, the susceptibility to suffer from aberrant chromosome segregation or to rewire the transcriptional landscape. The author declares no conflicts of interest.