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Key Points Eight new types of histone short-chain Lys acylations have been discovered in the past few years, which include Lys propionylation (Kpr), Lys butyrylation (Kbu), Lys 2-hydroxyisobutyrylation (Khib), Lys succinylation (Ksucc), Lys malonylation (Kma), Lys glutarylation (Kglu), Lys crotonylation (Kcr) and Lys β-hydroxybutyrylation (Kbhb). Histone Lys acylations are regulated by acyltransferases and deacylases. Histone Lys acylations are modulated by the cellular metabolism of cognate short-chain acyl-CoA species. The novel histone Lys acylations are recognized by specific protein domains and can be differentiated from Lys acetylation. Histone Lys acylations mark transcriptionally active genes and function in different physiological processes, such as signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. In addition to acetylation, eight types of structurally and functionally different short-chain acylations have recently been identified as important histone Lys modifications: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. These modifications are regulated by enzymatic and metabolic mechanisms and have physiological functions, which include signal-dependent gene activation and metabolic stress. Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this Review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.

Climate change affects physical and biogeochemical processes in lakes. We show significant increases in surface-water temperature (~ 0.5 °C decade −1 ; > 0.2% year −1 ) and wave power (> 1% year −1 ; the transport of energy by waves) associated with atmospheric phenomena (Atlantic Multidecadal Oscillation and Multivariate El Niño/Southern Oscillation) in the month of August between 1980 and 2018 in the Laurentian Great Lakes. A pattern in wave power, in response to extreme winds, was identified as a proxy to predict interbasin coupling in Lake Erie. This involved the upwelling of cold and hypoxic (dissolved oxygen < 2 mg L −1 ) hypolimnetic water containing high total phosphorus concentration from the seasonally stratified central basin into the normally well-mixed western basin opposite to the eastward flow. Analysis of historical records indicate that hypoxic events due to interbasin exchange have increased in the western basin over the last four decades (43% in the last 10 years) thus affecting the water quality of the one of the world’s largest freshwater sources and fisheries.

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases 1 , 2 . Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1 . Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer. The lactylation of lysine residues on histones in mammalian cells is stimulated by hypoxia and bacterial challenges, and increased histone lactylation induces genes involved in wound healing.

Metabolic regulation of histone marks is associated with diverse biological processes through dynamically modulating chromatin structure and functions. Here we report the identification and characterization of a histone mark, lysine benzoylation (K bz ). Our study identifies 22 K bz sites on histones from HepG2 and RAW cells. This type of histone mark can be stimulated by sodium benzoate (SB), an FDA-approved drug and a widely used chemical food preservative, via generation of benzoyl CoA. By ChIP-seq and RNA-seq analysis, we demonstrate that histone K bz marks are associated with gene expression and have physiological relevance distinct from histone acetylation. In addition, we demonstrate that SIRT2, a NAD + -dependent protein deacetylase, removes histone K bz both in vitro and in vivo. This study therefore reveals a new type of histone marks with potential physiological relevance and identifies possible non-canonical functions of a widely used chemical food preservative. Histone marks regulate chromatin structure and function. Here the authors identify and characterize lysine benzoylation, a histone mark that can be modulated by sodium benzoate, a widely used chemical food preservative, associated with specific regulation of gene expression.

Post-translational modifications are critical to protein structure and function. Mass spectrometry, antibody pulldowns and other lines of evidence now establish the presence of lysine succinylation across numerous proteins and species. Of the 20 ribosomally coded amino acid residues, lysine is the most frequently post-translationally modified, which has important functional and regulatory consequences. Here we report the identification and verification of a previously unreported form of protein post-translational modification (PTM): lysine succinylation. The succinyllysine residue was initially identified by mass spectrometry and protein sequence alignment. The identified succinyllysine peptides derived from in vivo proteins were verified by western blot analysis, in vivo labeling with isotopic succinate, MS/MS and HPLC coelution of their synthetic counterparts. We further show that lysine succinylation is evolutionarily conserved and that this PTM responds to different physiological conditions. Our study also implies that succinyl-CoA might be a cofactor for lysine succinylation. Given the apparent high abundance of lysine succinylation and the significant structural changes induced by this PTM, it is expected that lysine succinylation has important cellular functions.

Short-chain fatty acids and their corresponding acyl-CoAs sit at the crossroads of metabolic pathways and play important roles in diverse cellular processes. They are also precursors for protein post-translational lysine acylation modifications. A noteworthy example is the newly identified lysine 2-hydroxyisobutyrylation （Khib） that is derived from 2-hydroxyisobutyrate and 2-hydroxyisobutyryl-CoA. Histone Khib has been shown to be associated with active gene expression in spermatogenic cells. However, the key elements that regulate this post-translational lysine acyla- tion pathway remain unknown. This has hindered characterization of the mechanisms by which this modification exerts its biological functions. Here we show that Esalp in budding yeast and its homologue Tip60 in human could add Khib to substrate proteins both in vitro and in vivo. In addition, we have identified HDAC2 and HDAC3 as the major enzymes to remove Khmb. Moreover, we report the first global profiling of Khib proteome in mammalian cells, identifying 6 548 Khb sites on 1 725 substrate proteins. Our study has thus discovered both the ＂writers＂ and ＂erasers＂ for histone Kh~b marks, and major Khib protein substrates. These results not only illustrate the landscape of this new lysine acylation pathway, but also open new avenues for studying diverse functions of cellular metabolites associated with this pathway.

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a \"don't eat me\" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.

This paper presents the design of an airborne DMD-based dual-path multi-target imaging spectrometer that is capable of achieving instantaneous imaging over a two-dimensional large field of view and the simultaneous spectral analysis of thousands of targets. It also offers advantages such as high spatial resolution, high spectral resolution, high timeliness, and low platform requirements. However, its working mechanism inherently causes misalignment errors in the dual-path images that it obtains due to exposure time differences. To address this issue, we propose a dual-path exposure time difference compensation method based on a velocity vector field model, enabling dynamic and precise matching of the dual paths. For target image points that move beyond the field of view, we propose an attitude compensation method based on optimal angular velocity coordination. Monte Carlo simulation results show that the maximum root mean square error of the compensation method across the entire field of view is 0.9792 pixels in the x-direction and 0.7130 pixels in the y-direction. Experimental results demonstrate the effectiveness of the method, which meets the requirements for practical applications and provides a reliable foundation for the real-world implementation of dual-path multi-target imaging spectrometers.

Constructing a synthetic community system helps scientist understand the complex interactions among species in a community and its environment. Herein, a two-species community is constructed with species A (artificial cells encapsulating pH-responsive molecules and sucrose) and species B ( Saccharomyces cerevisiae ), which causes the environment to exhibit pH oscillation behaviour due to the generation and dissipation of CO 2 . In addition, a three-species community is constructed with species A′ (artificial cells containing sucrose and G6P), species B, and species C (artificial cells containing NAD + and G6PDH). The solution pH oscillation regulates the periodical release of G6P from species A′; G6P then enters species C to promote the metabolic reaction that converts NAD + to NADH. The location of species A′ and B determines the metabolism behaviour in species C in the spatially coded three-species communities with CA′B, CBA′, and A′CB patterns. The proposed synthetic community system provides a foundation to construct a more complicated microecosystem. Most synthetic communities are unidirectional or two-way interaction without dynamic feedback. Here, the authors report a dynamic feedback system involving artificial cell species, biological cell species, and their environment using pH-sensitive molecule that phase-shift between fluid and gel phases.

Hypoxic conditions continue to be an environmental concern in lakes, including those with shallow and well-mixed basins, such as the western basin of Lake Erie, in which hypoxia is not anticipated. We investigated the dynamics and causes of hypoxia using field measurements at two locations in the western basin during the late summer of 2017. Two hypoxic events (dissolved oxygen [DO] concentrations < 2 mg L−1) were recorded that were caused by upwelling of hypolimnetic water from the central basin of the lake following winds from the south and southwest. In this case, instantaneous stratification occurred when cool central basin water (i.e., 15.7°C) intruded as a 2.5-m-thick layer above the bottom under the warm western basin waters (i.e., 23.9°C). A third hypoxic event, which was associated with more typical thermal stratification from atmospheric warming, occurred during a calm and warm period near the end of the deployment. In this case, we observed a continuous decline in hypolimnetic DO from ≈ 8 to < 5 mg L−1, which likely declined to < 2 mg L−1 in 14 d using a one-dimensional model. Interbasin exchange flows generated instantaneous hypoxia multiple times within a year and were the dominate cause (63% of 11 cases) of hypoxia identified during August fishing trawls in the study area over the past 30 yr. Results of this work should help with the prediction and understanding of hypoxia in lakes with multiple basins, which will be informative for water quality and fisheries management.