Cellular Metabolites Research Articles

Ocean acidification affects pigment concentration and photoprotection of marine phytoplankton

AbstractOcean acidification produces significant changes on phytoplankton physiology that can affect their growth and primary production. Among them, a downregulation of the enzymatic activity and the production of different cellular metabolites, including chlorophyll a (Chl a), has been observed in high CO2 cultures under stable conditions. However, the extent of how phytoplankton metabolism regulation under high CO2 conditions affects pigment pools and patterns is unknown. This study shows the effect of the atmospheric CO2 increase on pigment concentration of three important marine primary producers: Thalassiosira pseudonana, Skeletonema costatum, and Emiliania huxleyi. Cultures grown under saturating photosynthetically active radiation were aerated for at least 3 weeks with current concentrations of atmospheric CO2 (0.04% CO2 in air) and with CO2 concentrations expected for future scenarios of climate change (0.1% CO2 in air) to assess the effect of CO2 under acclimated metabolism and stable conditions. Moreover, cultures were also subjected to a perturbation (4 h without aeration) to assess responses under non‐stable conditions. The results showed that light harvesting and photoprotective pigment concentrations (i.e., Chl a, Chl c2, ββ‐carotene, diadinoxanthin, diatoxanthin, fucoxanthin, among others) decreased significantly under high CO2 and stable conditions, but the response reversed after the perturbation. The de‐epoxidation state of xanthophylls, also showed similar patterns, indicating an increase in phytoplankton sensitivity under high CO2 and stable conditions. The results demonstrate the relevance of CO2 concentration and acclimation status for phytoplankton light absorption and photoprotective response. They also identify fucoxanthin and Chl c2 as suitable biomarkers of phytoplankton carbon metabolism under ocean acidification conditions.

Mass Spectrometry Reveals High Levels of Hydrogen Peroxide in Pancreatic Cancer Cells

AbstractReactive oxygen species (ROS) are critical for many cellular functions, and dysregulation of ROS involves the development of multiple types of tumors, including pancreatic cancer. However, ROS have been grouped into a single biochemical entity for a long time, and the specific roles of certain types of ROS in tumor cells (e.g., pancreatic ductal adenocarcinoma (PDAC)) have not been systematically investigated. In this work, a highly sensitive and accurate mass spectrometry‐based method was applied to study PDAC cells of humans and of genetically modified animals. The results show that the oncogenic KRAS mutation promotes the accumulation of hydrogen peroxide (H2O2) rather than superoxide or hydroxyl radicals in pancreatic cancer cells. We further identified that the enriched H2O2 modifies cellular metabolites and promotes the survival of pancreatic cancer cells. These findings highlight the specific roles of H2O2 in pancreatic cancer development, which may provide new directions for pancreatic cancer therapy.

Mass Spectrometry Reveals High Levels of Hydrogen Peroxide in Pancreatic Cancer Cells.

Reactive oxygen species (ROS) are critical for many cellular functions, and dysregulation of ROS involves the development of multiple types of tumors, including pancreatic cancer. However, ROS have been grouped into a single biochemical entity for a long time, and the specific roles of certain types of ROS in tumor cells (e.g., pancreatic ductal adenocarcinoma (PDAC)) have not been systematically investigated. In this work, a highly sensitive and accurate mass spectrometry-based method was applied to study PDAC cells of humans and of genetically modified animals. The results show that the oncogenic KRAS mutation promotes the accumulation of hydrogen peroxide (H2 O2 ) rather than superoxide or hydroxyl radicals in pancreatic cancer cells. We further identified that the enriched H2 O2 modifies cellular metabolites and promotes the survival of pancreatic cancer cells. These findings highlight the specific roles of H2 O2 in pancreatic cancer development, which may provide new directions for pancreatic cancer therapy.

A cellular metabolite directly and reversibly opens the ATP release pannexin channels.

Pannexins (Panx1-3) are a broadly expressed family of ion channels which mediate the cellular release of signaling molecules such as ATP. There are many established roles of pannexins in cell signaling and pathophysiology, particularly in the immune, cardiovascular, and nervous systems. Notably, Panx1 opens irreversibly following cleavage of its C-terminus by caspases in apoptotic cells, releasing ATP to recruit nearby phagocytes. However, there are many signaling roles of pannexin in non-apoptotic cells, which dictates that a reversible mode of activation must exist. To date, a number of post-translational modifications have been proposed as such candidates. Nevertheless, these findings typically relied on cell-based experiments and the simultaneous use of large, supraphysiological voltages to assess changes in channel function. Thus, it is unclear whether they act themselves as a channel gating stimulus or act as modulators. Based on our previous work, we postulated that small molecules may act as a natural gating stimulus for pannexins. An unbiased screen of cellular metabolites obtained from mouse tissues revealed a candidate pannexin agonist. Electrophysiological, cell-based, and in vitro assays confirmed that these metabolites act directly on pannexins to reversibly open the channel and trigger ATP release at resting membrane potential. These data establish this molecule class as the first bona fide pannexin agonists, and elucidate a novel biochemical pathway leading to ATP release through pannexins.

A 640 × 640 ISFET array for detecting cell metabolism

Ion sensitive field effect transistor (ISFET) devices are highly accurate, convenient, fast and low-cost in the detection of ions and biological macromolecules, such as DNA molecules, antibodies, enzymatic substrates and cellular metabolites. For high-throughput cell metabolism detection, we successfully designed a very large-scale biomedical sensing application specific integrated circuit (ASIC) with a 640 × 640 ISFET array. The circuit design is highly integrated by compressing the size of a pixel to 7.4 × 7.4 μm2 and arranging the layout of even and odd columns in an interdigital pattern to maximize the utilization of space. The chip can operate at a speed of 2.083M pixels/s and the dynamic process of the fluid flow on the surface of the array was monitored through ion imaging. The pH sensitivity is 33 ± 4 mV/pH and the drift rate is 0.06 mV/min after 5 h, indicating the stability and robustness of the chip. Moreover, the chip was applied to monitor pH changes in CaSki cells metabolism, with pH shifting from 8.04 to 7.40 on average. This platform has the potential for continuous and parallel monitoring of cell metabolism in single-cell culture arrays.

Chemical probing profiling of 2'-deoxyguanosine sensing RNA reveals magnesium ion-dependent conformational switching.

Maintaining the homeostasis of cellular metabolites is essential for all living organisms. Noncoding mRNA in procaryotes strategically regulates the expression of downstream genes which are linked to the expression of proteins involved in specific metabolite salvage and biosynthesis, in response to binding to that specific metabolite. Such noncoding mRNAs are known as the Riboswitches. A class of riboswitches that recognizes purine analogs were identified. In this present contribution, we report the influence of magnesium and temperature on the conformation of the aptamer domain (the ligand binding domain) of 2’-deoxyguanosine riboswitch from Mesoplasma florum. Our comprehensive SHAPE (Selective 2′ Hydroxyl Acylation analyzed by Primer Extension) probing experiments have shown that the aptamer domain exhibited a strong dependence on the Mg2+ ion concentration for the efficient ligand binding and the concomitant structural change. Mg2+ ions reduce the conformational flexibility mainly by organizing P2 and P3 helices and thereby facilitate ligand binding by shifting the conformational ensemble of the ligand-free aptamer towards a pre-organized, ligand-binding competent conformation. The subtle conformational switching in the presence and absence of 2’-deoxyguanosine is observed at the (A) regulatory helix (P1) and (B) the interhelical junctions (which serve as the ligand binding pocket) of the aptamer. We have observed the formation of a regulatory helix, the folding of the binding pocket, and the subsequent encapsulation of the ligand is accomplished only in the simultaneous presence of Mg2+ and 2’-deoxyguanosine. We have also identified the existence of two conformations in equilibrium in a ligand-free state. Finally, we have shown that for the 2’-dG sensing riboswitch from Mesoplasma forum, the conformation of the full-length transcripts populates the functional OFF-state regardless of the presence or absence of ligand, consistent with a kinetic riboswitch mechanism.

A Systematic Review Of Metallic Nanoparticles: Synthesis, Biological Activities & Applications

Metallic nanoparticles (MNP) have captivated scientist for over a century and are now profoundly utilized in biomedical sciences and engineering. MNPs interact with key cellular organelles and biomolecules, including DNA, enzymes, ribosomes, and liposomes, which can have an impact on gene expression, oxidative stress, protein and enzyme activation, and cell membrane permeability. It has been shown that the cellular metabolites of living organisms like bacteria, yeast, fungi, and plant cells can convert inorganic metal ions into metal NPs. By utilizing biological agents in green chemistry, metallic nanoparticles are produced that have less adverse effects and are more effective against cancer cells. These nanoparticles can physically infiltrate cancer cells and kill them by activating a variety of biochemical pathways, including apoptosis, necrosis, and autophagy. This review focuses on metal nanoparticles (copper, gold, and silver) and their usefulness in treating endemic diseases including cancer, hepatitis, and malaria. In the near future, metal NPs may also be a successful and affordable alternative for treating drug-resistant bacterial infections.

The structural features of the ligand-free moaA riboswitch and its ion-dependent folding

Riboswitches are structural elements of mRNA involved in the regulation of gene expression by responding to specific cellular metabolites. To fulfil their regulatory function, riboswitches prefold into an active state, the so-called binding competent form, that guarantees metabolite binding and allows a consecutive refolding of the RNA. Here, we describe the folding pathway to the binding competent form as well as the ligand free structure of the moaA riboswitch of E. coli. This RNA proposedly responds to the molybdenum cofactor (Moco), a highly oxygen-sensitive metabolite, essential in the carbon and sulfur cycles of eukaryotes. K+- and Mg2+-dependent footprinting assays and spectroscopic investigations show a high degree of structure formation of this RNA already at very low ion-concentrations. Mg2+ facilitates additionally a general compaction of the riboswitch towards its proposed active structure. We show that this fold agrees with the earlier suggested secondary structure which included also a long-range tetraloop/tetraloop-receptor like interaction. Metal ion cleavage assays revealed specific Mg2+-binding pockets within the moaA riboswitch. These Mg2+ binding pockets are good indicators for the potential Moco binding site, since in riboswitches, Mg2+ was shown to be necessary to bind phosphate-carrying metabolites. The importance of the phosphate and of other functional groups of Moco is highlighted by binding assays with tetrahydrobiopterin, the reduced and oxygen-sensitive core moiety of Moco. We demonstrate that the general molecular shape of pterin by its own is insufficient for the recognition by the riboswitch.

Phytohormones enhance heavy metal responses in Euglena gracilis: Evidence from uptake of Ni, Pb and Cd and linkages to hormonomic and metabolomic dynamics

Over the last decade, significant effort has been made to understand phytohormonal functions (e.g., cytokinins (CKs) and abscisic acid (ABA)) in metal stress responses of higher plants and algae. Despite the potential for these phytohormones to improve industrial remediation by Euglena gracilis (Euglenophyceae), no such roles have been elucidated for this highly adaptive species and its response to heavy metals. This study demonstrates that toxic metals (nickel, lead, cadmium) modify hormonal activity profiles (i.e., CK forms and their concentrations) in E. gracilis. Furthermore, exogenous ABA or CK (tZ) enabled higher metal uptake efficiency (i.e., 9.35% in lead and 9.2% in cadmium uptake with CK) and alleviated metal toxicity through the regulation of endogenous CKs (i.e., total CK, isoprenoid CK) and gibberellin (GAs, GA1 and GA3) levels. These responses suggest that E. gracilis regulates multiple phytohormone signals during metal stress acclimation. A deeper approach, using untargeted metabolomic analyses, gave more detailed insight into phytohormone-controlled pathways and associated modified metabolites, which were frequently related to metal accumulation and the physiological acclimation to metal presence. Significant changes in the levels of cellular metabolites, especially those involved in acclimation to metal stress, were under the influence of phytohormones in algal cells. When grown under metal stress conditions, the presence of exogenous ABA or CKs, caused changes in cellular metabolites which included those from: lipid pathways, riboflavin metabolism, the biosynthesis of cofactors/vitamins, and carbohydrate metabolism. Also, bioactive secondary metabolites (e.g., terpenoids, alkaloids, flavonoids, carotenoids) were modified in algal cells treated with phytohormones. Thus, the study gives a detailed view on the regulatory functions of ABA and CKs in algal metal bioremediation strategies, which are attributed to enhanced metal uptake and in the fine-tuning of plant hormone levels during metal stress response. The results can guide efforts to develop efficient, low-cost and environmentally friendly methods for bioremediation.

Full activation of thermogenesis in brown adipocytes requires Basigin action.

Exploring mechanisms responsible for brown adipose tissue's (BAT) high metabolic activity is crucial to exploit its energy-dissipating ability for therapeutic purposes. Basigin (Bsg), a multifunctional highly glycosylated transmembrane protein, was recently proposed as one of the 98 critical markers allowing to distinguish 'white' and 'brown' adipocytes, yet its function in thermogenic brown adipocytes is unknown. Here, we report that Bsg is negatively associated with obesity in mice. By contrast, Bsg expression increased in the mature adipocyte fraction of BAT upon cold acclimation. Additionally, Bsg levels were highly induced during brown adipocyte maturation in vitro and were further increased upon β-adrenergic stimulation in a HIF-1α-dependent manner. siRNA-mediated Bsg gene silencing in cultured brown adipocytes did not impact adipogenesis nor mitochondrial function. However, a significant decrease in mitochondrial respiration, lipolysis and Ucp1 transcription was observed in adipocytes lacking Bsg, when activated by norepinephrine. Furthermore, using gas chromatography/mass spectrometry-time-of-flight analysis to assess the composition of cellular metabolites, we demonstrate that brown adipocytes lacking Bsg have lower levels of intracellular lactate and acetoacetate. Bsg was additionally required to regulate intracellular AcAc and tricarboxylic acid cycle intermediate levels in NE-stimulated adipocytes. Our study highlights the critical role of Bsg in active brown adipocytes, possibly by controlling cellular metabolism.

Role of Exosomes and Their Potential as Biomarkers in Epstein-Barr Virus-Associated Gastric Cancer.

Exosomes are a subtype of extracellular vesicles ranging from 30 to 150 nm and comprising many cellular components, including DNA, RNA, proteins, and metabolites, encapsulated in a lipid bilayer. Exosomes are secreted by many cell types and play important roles in intercellular communication in cancer. Viruses can hijack the exosomal pathway to regulate viral propagation, cellular immunity, and the microenvironment. Cells infected with Epstein-Barr virus (EBV), one of the most common oncogenic viruses, have also been found to actively secrete exosomes, and studies on their roles in EBV-related malignancies are ongoing. In this review, we focus on the role of exosomes in EBV-associated gastric cancer and their clinical applicability in diagnosis and treatment.

HIV-1 is dependent on its immature lattice to recruit IP6 for mature capsid assembly.

HIV-1 Gag metamorphoses inside each virion, from an immature lattice that forms during viral production to a mature capsid that drives infection. Here we show that the immature lattice is required to concentrate the cellular metabolite inositol hexakisphosphate (IP6) into virions to catalyze mature capsid assembly. Disabling the ability of HIV-1 to enrich IP6 does not prevent immature lattice formation or production of the virus. However, without sufficient IP6 molecules inside each virion, HIV-1 can no longer build a stable capsid and fails to become infectious. IP6 cannot be replaced by other inositol phosphate (IP) molecules, as substitution with other IPs profoundly slows mature assembly kinetics and results in virions with gross morphological defects. Our results demonstrate that while HIV-1 can become independent of IP6 for immature assembly, it remains dependent upon the metabolite for mature capsid formation.

Vacuolar Processing Enzymes in Plant Programmed Cell Death and Autophagy.

Vacuolar processing enzymes (VPEs) are plant cysteine proteases that are subjected to autoactivation in an acidic pH. It is presumed that VPEs, by activating other vacuolar hydrolases, are in control of tonoplast rupture during programmed cell death (PCD). Involvement of VPEs has been indicated in various types of plant PCD related to development, senescence, and environmental stress responses. Another pathway induced during such processes is autophagy, which leads to the degradation of cellular components and metabolite salvage, and it is presumed that VPEs may be involved in the degradation of autophagic bodies during plant autophagy. As both PCD and autophagy occur under similar conditions, research on the relationship between them is needed, and VPEs, as key vacuolar proteases, seem to be an important factor to consider. They may even constitute a potential point of crosstalk between cell death and autophagy in plant cells. This review describes new insights into the role of VPEs in plant PCD, with an emphasis on evidence and hypotheses on the interconnections between autophagy and cell death, and indicates several new research opportunities.

Potential of Suaeda nudiflora and Suaeda fruticosa to Adapt to High Salinity Conditions

The deposition of salts in soil seems likely to become a significant barrier for plant development and growth. Halophytes that flourish in naturally saline habitats may sustain extreme salt levels by adopting different acclimatory traits. Insight into such acclimatory features can be useful for devising salt-resilient crops and the reclamation of saline soil. Therefore, salinity-induced responses were studied in two halophytes, i.e., Suaeda nudiflora and Suaeda fruticosa, at a high soil salinity level (ECe 65) to explore their possible tolerance mechanisms in their natural habitat. Samples of different tissues were collected from both Suaeda species for the determination of physio-biochemical attributes, i.e., ionic (Na+, K+, Ca2+, Cl−) content, osmo-protective compounds (proline, soluble sugars, soluble proteins), total phenolic content, and antioxidant components. Heavy metal composition and accumulation in soil and plant samples were also assessed, respectively. Fourier transform infrared spectroscopy (FTIR) analysis was conducted to explore cellular metabolite pools with respect to high salinity. The results showed that both species considerably adjusted the above-mentioned physio-biochemical attributes to resist high salinity, demonstrated by quantitative differences in their above-ground tissues. The FTIR profiles confirmed the plants’ differential responses in terms of variability in lipids, proteins, carbohydrates, and cell wall constituents. The high capacity for Na+ and Cl− accumulation and considerable bioaccumulation factor (BAF) values for metals, mainly Fe and Zn, validate the importance of both Suaeda species as phytodesalination plants and their potential use in the phytoremediation of salt- and metal-polluted soils.

Methylotroph bacteria and cellular metabolite carotenoid alleviate ultraviolet radiation-driven abiotic stress in plants.

Increasing UV radiation in the atmosphere due to the depletion of ozone layer is emerging abiotic stress for agriculture. Although plants have evolved to adapt to UV radiation through different mechanisms, but the role of phyllosphere microorganisms in counteracting UV radiation is not well studied. The current experiment was undertaken to evaluate the role of phyllosphere Methylobacteria and its metabolite in the alleviation of abiotic stress rendered by ultraviolet (UV) radiation. A potential pink pigmenting methylotroph bacterium was isolated from the phylloplane of the rice plant (oryzae sativa). The 16S rRNA gene sequence of the bacterium was homologous to the Methylobacter sp. The isolate referred to as Methylobacter sp N39, produced beta-carotene at a rate (μg ml-1 d-1) of 0.45-3.09. Biosynthesis of beta-carotene was stimulated by brief exposure to UV for 10 min per 2 days. Carotenoid biosynthesis was predicted as y = 3.09 × incubation period + 22.151 (r 2 = 0.90). The carotenoid extract of N39 protected E. coli from UV radiation by declining its death rate from 14.67% min-1 to 4.30% min-1 under UV radiation. Application of N39 cells and carotenoid extract also protected rhizobium (Bradyrhizobium japonicum) cells from UV radiation. Scanning electron microscopy indicated that the carotenoid extracts protected E. coli cells from UV radiation. Foliar application of either N39 cells or carotenoid extract enhanced the plant's (Pigeon pea) resistance to UV irradiation. This study highlight that Methylobacter sp N39 and its carotenoid extract can be explored to manage UV radiation stress in agriculture.

Alpha-ketoglutarate partially alleviates effects of high-fat high-fructose diet in mouse muscle.

Consumption of high-calorie diets leads to excessive accumulation of storage lipids in adipose tissue. Metabolic changes occur not only in adipose tissue but in other tissues, too, such as liver, heart, muscle, and brain. This study aimed to explore the effects of high-fat high-fructose diet (HFFD) alone and in the combination with alpha-ketoglutarate (AKG), a well-known cellular metabolite, on energy metabolism in the skeletal muscle of C57BL/6J mice. Five-month-old male mice were divided into four groups - the control one fed a standard diet (10 % kcal fat), HFFD group fed a high-fat high-fructose diet (45 % kcal fat, 15 % kcal fructose), AKG group fed a standard diet with 1 % sodium AKG in drinking water, and HFFD + AKG group fed HFFD and water with 1 % sodium AKG. The dietary regimens lasted 8 weeks. Mice fed HFFD had higher levels of storage triacylglycerides, lower levels of glycogen, and total water-soluble protein, and higher activities of key glycolytic enzymes, namely hexokinase, phosphofructokinase, and pyruvate kinase, as compared with the control group. The results suggest that muscles of HFFD mice may suffer from lipotoxicity. In HFFD + AKG mice, levels of the metabolites and activities of glycolytic enzymes did not differ from the respective values in the control group, except for the activity of pyruvate kinase, which was significantly lower in HFFD + AKG group compared with the control. Thus, metabolic changes in mouse skeletal muscles, caused by HFFD, were alleviated by AKG, indicating a protective role of AKG regarding lipotoxicity.

PLEKHG2 Promotes NSCLC Cell Growth by Increasing Glycolysis via Activated PI3K/AKT Pathway.

Purpose: PLEKHG2 is a member of the diffuse B-cell lymphoma family. The function of PLEKHG2 in NSCLC was still unclear. This study aimed to investigate the relationship between the upregulated expression of PLEKHG2 and the prognosis of NSCLC and to revealed its mechanisms. Materials and methods: The expression of PLEKHG2 in NSCLC patients and its relationship with prognosis were first determined by analyzing public databases. Validation was performed in NSCLC cell lines and patient`s tumor tissues. PLEKHG2-silenced H1299 cells and PLEKHG2 overexpressing PC9 cells were constructed and used to validate its function. Glycolysis was evaluated by assaying cellular metabolites, glucose uptake and the expression levels of biomarkers of glycolysis. The relationship of PLEKHG2 and the PI3K/Akt pathway was demonstrated by small molecule inhibitors. The function of PLEKHG2 was evaluated in vivo by a H1299 cell derived xenograft (CDX) model. Results: PLEKEHG2 was highly expressed in NSCLC tissues and associated with poor prognosis. In PLEKHG2 knockdown H1299 cells, ATP and lactate production and glucose uptake were significantly inhibited. The opposite results were observed in PC9 cells with PLEKHG2 overexpression. The increased glycolysis following PLEKHG2 overexpression was abolished by adding the PI3K/AKT pathway inhibitor LY294002, suggesting that PLEKHG2 promotes glycolysis in NSCLC cells via activation of the PI3K/AKT pathway. Finally, we found that PLEKHG2 knockdown inhibited the tumor growth in the H1299 CDX model. Conclusion: PLEKHG2 contributed to NSCLC development by promoting glycolysis via activation of the PI3K/AKT pathway. PLEKHG2 was a potential therapeutic target and biomarker for poor prognosis of NSCLC.

Evidence of Cytolysin A nanopore incorporation in mammalian cells assessed by a graphical user interface.

Technologies capable of assessing cellular metabolites with high precision and temporal resolution are currently limited. Recent developments in the field of nanopore sensors allow the non-stochastic quantification of metabolites, where a nanopore is acting as an electrical transducer for selective substrate binding proteins (SBPs). Here we show that incorporation of the pore-forming toxin Cytolysin A (ClyA) into the plasma membrane of Chinese hamster ovary cells (CHO-K1) results in the appearance of single-channel conductance amenable to multiplexed automated patch-clamp (APC) electrophysiology. In CHO-K1 cells, SBPs modify the ionic current flowing though ClyA nanopores, thus demonstrating its potential for metabolite sensing of living cells. Moreover, we developed a graphical user interface for the analysis of the complex signals resulting from multiplexed APC recordings. This system lays the foundation to bridge the gap between recent advances in the nanopore field (e.g., proteomic and transcriptomic) and potential cellular applications.

Chemical sensors for imaging total cellular aliphatic aldehydes in live cells.

Aliphatic aldehydes are reactive electrophilic carbonyls that cross-link with DNA and proteins leading to cellular toxicity and disease pathogenesis. This toxicity is due to the cooperative effect of multiple aldehydes via a common mechanism. Therefore, live-cell imaging of total aliphatic aldehydes, small-to-long chain (C1-C10), is highly desired to decipher their physiological and pathological functions. However, sensors for imaging total cellular aliphatic aldehydes are currently lacking despite their high concentrations (∼80 to >500 μM) inside cells. Herein, we report chemical sensors that generate a benzimidazole moiety upon reaction with aliphatic aldehydes of different chain lengths (C1-C10), resulting in turn-on fluorescence. These sensors exhibit high quantum yields, high dynamic range, and enable the quantification of changes in both the exogenous administration of aldehydes and endogenous real-time formation of aliphatic aldehydes in live mammalian cells. This tool has great potential to transform aldehyde research by illuminating cellular metabolites that have remained elusive in living systems.

G-quadruplexes sense natural porphyrin metabolites for regulation of gene transcription and chromatin landscapes

BackgroundG-quadruplexes (G4s) are unique noncanonical nucleic acid secondary structures, which have been proposed to physically interact with transcription factors and chromatin remodelers to regulate cell type-specific transcriptome and shape chromatin landscapes.ResultsBased on the direct interaction between G4 and natural porphyrins, we establish genome-wide approaches to profile where the iron-liganded porphyrin hemin can bind in the chromatin. Hemin promotes genome-wide G4 formation, impairs transcription initiation, and alters chromatin landscapes, including decreased H3K27ac and H3K4me3 modifications at promoters. Interestingly, G4 status is not involved in the canonical hemin-BACH1-NRF2-mediated enhancer activation process, highlighting an unprecedented G4-dependent mechanism for metabolic regulation of transcription. Furthermore, hemin treatment induces specific gene expression profiles in hepatocytes, underscoring the in vivo potential for metabolic control of gene transcription by porphyrins.ConclusionsThese studies demonstrate that G4 functions as a sensor for natural porphyrin metabolites in cells, revealing a G4-dependent mechanism for metabolic regulation of gene transcription and chromatin landscapes, which will deepen our knowledge of G4 biology and the contribution of cellular metabolites to gene regulation.