Structural basis of human ACE2 higher binding affinity to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1.

The currently circulating Omicron sub-variants are the SARS-CoV-2 strains with the highest number of known mutations. Herein, we found that human angiotensin-converting enzyme 2 (hACE2) binding affinity to the receptor-binding domains (RBDs) of the four early Omicron sub-variants (BA.1, BA.1.1, BA.2, and BA.3) follows the order BA.1.1 > BA.2 > BA.3 ≈ BA.1. The complex structures of hACE2 with RBDs of BA.1.1, BA.2, and BA.3 reveal that the higher hACE2 binding affinity of BA.2 than BA.1 is related to the absence of the G496S mutation in BA.2. The R346K mutation in BA.1.1 majorly affects the interaction network in the BA.1.1 RBD/hACE2 interface through long-range alterations and contributes to the higher hACE2 affinity of the BA.1.1 RBD than the BA.1 RBD. These results reveal the structural basis for the distinct hACE2 binding patterns among BA.1.1, BA.2, and BA.3 RBDs.

Nociceptor-immune interactomes reveal insult-specific immune signatures of pain.

Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.

The rise of baobab trees in Madagascar.

The baobab trees (genus Adansonia) have attracted tremendous attention because of their striking shape and distinctive relationships with fauna1. These spectacular trees have also influenced human culture, inspiring innumerable arts, folklore and traditions. Here we sequenced genomes of all eight extant baobab species and argue that Madagascar should be considered the centre of origin for the extant lineages, a key issue in their evolutionary history2,3. Integrated genomic and ecological analyses revealed the reticulate evolution of baobabs, which eventually led to the species diversity seen today. Past population dynamics of Malagasy baobabs may have been influenced by both interspecific competition and the geological history of the island, especially changes in local sea levels. We propose that further attention should be paid to the conservation status of Malagasy baobabs, especially of Adansonia suarezensis and Adansonia grandidieri, and that intensive monitoring of populations of Adansonia za is required, given its propensity for negatively impacting the critically endangered Adansonia perrieri.

Ladderphane copolymers for high-temperature capacitive energy storage.

For capacitive energy storage at elevated temperatures1-4, dielectric polymers are required to integrate low electrical conduction with high thermal conductivity. The coexistence of these seemingly contradictory properties remains a persistent challenge for existing polymers. We describe here a class of ladderphane copolymers exhibiting more than one order of magnitude lower electrical conductivity than the existing polymers at high electric fields and elevated temperatures. Consequently, the ladderphane copolymer possesses a discharged energy density of 5.34 J cm-3 with a charge-discharge efficiency of 90% at 200 °C, outperforming the existing dielectric polymers and composites. The ladderphane copolymers self-assemble into highly ordered arrays by π-π stacking interactions5,6, thus giving rise to an intrinsic through-plane thermal conductivity of 1.96 ± 0.06 W m-1 K-1. The high thermal conductivity of the copolymer film permits efficient Joule heat dissipation and, accordingly, excellent cyclic stability at elevated temperatures and high electric fields. The demonstration of the breakdown self-healing ability of the copolymer further suggests the promise of the ladderphane structures for high-energy-density polymer capacitors operating under extreme conditions.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons.

The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.

A Mettl16/m6A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells.

Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development.

Pivotal role of reversible NiO6 geometric conversion in oxygen evolution.

Realizing an efficient electron transfer process in the oxygen evolution reaction by modifying the electronic states around the Fermi level is crucial in developing high-performing and robust electrocatalysts1-3. Typically, electron transfer proceeds solely through either a metal redox chemistry (an adsorbate evolution mechanism (AEM), with metal bands around the Fermi level) or an oxygen redox chemistry (a lattice oxygen oxidation mechanism (LOM), with oxygen bands around the Fermi level), without the concurrent occurrence of both metal and oxygen redox chemistries in the same electron transfer pathway1-15. Here we report an electron transfer mechanism that involves a switchable metal and oxygen redox chemistry in nickel-oxyhydroxide-based materials with light as the trigger. In contrast to the traditional AEM and LOM, the proposed light-triggered coupled oxygen evolution mechanism requires the unit cell to undergo reversible geometric conversion between octahedron (NiO6) and square planar (NiO4) to achieve electronic states (around the Fermi level) with alternative metal and oxygen characters throughout the oxygen evolution process. Utilizing this electron transfer pathway can bypass the potential limiting steps, that is, oxygen-oxygen bonding in AEM and deprotonation in LOM1-5,8. As a result, the electrocatalysts that operate through this route show superior activity compared with previously reported electrocatalysts. Thus, it is expected that the proposed light-triggered coupled oxygen evolution mechanism adds a layer of understanding to the oxygen evolution research scene.

Non-genetic determinants of malignant clonal fitness at single-cell resolution.

All cancers emerge after a period of clonal selection and subsequent clonal expansion. Although the evolutionary principles imparted by genetic intratumour heterogeneity are becoming increasingly clear1, little is known about the non-genetic mechanisms that contribute to intratumour heterogeneity and malignant clonal fitness2. Here, using single-cell profiling and lineage tracing (SPLINTR)-an expressed barcoding strategy-we trace isogenic clones in three clinically relevant mouse models of acute myeloid leukaemia. We find that malignant clonal dominance is a cell-intrinsic and heritable property that is facilitated by the repression of antigen presentation and increased expression of the secretory leukocyte peptidase inhibitor gene (Slpi), which we genetically validate as a regulator of acute myeloid leukaemia. Increased transcriptional heterogeneity is a feature that enables clonal fitness in diverse tissues and immune microenvironments and in the context of clonal competition between genetically distinct clones. Similar to haematopoietic stem cells3, leukaemia stem cells (LSCs) display heritable clone-intrinsic properties of high, and low clonal output that contribute to the overall tumour mass. We demonstrate that LSC clonal output dictates sensitivity to chemotherapy and, although high- and low-output clones adapt differently to therapeutic pressure, they coordinately emerge from minimal residual disease with increased expression of the LSC program. Together, these data provide fundamental insights into the non-genetic transcriptional processes that underpin malignant clonal fitness and may inform future therapeutic strategies.

Intrinsic tensile ductility in strain hardening multiprincipal element metallic glass.

Traditional metallic glasses (MGs), based on one or two principal elements, are notoriously known for their lack of tensile ductility at room temperature. Here, we developed a multiprincipal element MG (MPEMG), which exhibits a gigapascal yield strength, significant strain hardening that almost doubles its yield strength, and 2% uniform tensile ductility at room temperature. These remarkable properties stem from the heterogeneous amorphous structure of our MPEMG, which is composed of atoms with significant size mismatch but similar atomic fractions. In sharp contrast to traditional MGs, shear banding in our glass triggers local elemental segregation and subsequent ordering, which transforms shear softening to hardening, hence resulting in shear-band self-halting and extensive plastic flows. Our findings reveal a promising pathway to design stronger, more ductile glasses that can be applied in a wide range of technological fields.

Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts.

Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

Splicing analysis of 24 potential spliceogenic variants in MMR genes and clinical interpretation based on refined ACMG/AMP criteria.

Lynch syndrome (LS) is a common hereditary cancer syndrome caused by heterozygous germline pathogenic variants in DNA mismatch repair (MMR) genes. Splicing defect constitutes one of the major mechanisms for MMR gene inactivation. Using RT-PCR based RNA analysis, we investigated 24 potential spliceogenic variants in MMR genes and determined their pathogenicity based on refined splicing-related American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. Aberrant transcripts were confirmed in 19 variants and 17 of which were classified as pathogenic including 11 located outside of canonical splice sites. Most of these variants were previously reported in LS patients without mRNA splicing assessment. Thus, our study provides crucial evidence for pathogenicity determination, allowing for appropriate clinical follow-up. We also found that computational predictions were globally well correlated with RNA analysis results and the use of both SPiP and SpliceAI software appeared more efficient for splicing defect prediction.

Phase separation-based visualization of protein-protein interactions and kinase activities in plants.

Protein activities depend heavily on protein complex formation and dynamic posttranslational modifications, such as phosphorylation. The dynamic nature of protein complex formation and posttranslational modifications is notoriously difficult to monitor in planta at cellular resolution, often requiring extensive optimization. Here, we generated and exploited the SYnthetic Multivalency in PLants (SYMPL)-vector set to assay protein-protein interactions (PPIs) (separation of phases-based protein interaction reporter) and kinase activities (separation of phases-based activity reporter of kinase) in planta, based on phase separation. This technology enabled easy detection of inducible, binary and ternary PPIs among cytoplasmic and nuclear proteins in plant cells via a robust image-based readout. Moreover, we applied the SYMPL toolbox to develop an in vivo reporter for SNF1-related kinase 1 activity, allowing us to visualize tissue-specific, dynamic SnRK1 activity in stable transgenic Arabidopsis (Arabidopsis thaliana) plants. The SYMPL cloning toolbox provides a means to explore PPIs, phosphorylation, and other posttranslational modifications with unprecedented ease and sensitivity.

Microglia-organized scar-free spinal cord repair in neonatal mice.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons1-4. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.

An antioxidant feedforward cycle coordinated by linker histone variant H1.2 and NRF2 that drives nonsmall cell lung cancer progression.

Nonsmall cell lung cancer (NSCLC) is highly malignant with limited treatment options, platinum-based chemotherapy is a standard treatment for NSCLC with resistance commonly seen. NSCLC cells exploit enhanced antioxidant defense system to counteract excessive reactive oxygen species (ROS), which contributes largely to tumor progression and resistance to chemotherapy, yet the mechanisms are not fully understood. Recent studies have suggested the involvement of histones in tumor progression and cellular antioxidant response; however, whether a major histone variant H1.2 (H1C) plays roles in the development of NSCLC remains unclear. Herein, we demonstrated that H1.2 was increasingly expressed in NSCLC tumors, and its expression was correlated with worse survival. When crossing the H1c knockout allele with a mouse NSCLC model (KrasLSL-G12D/+), H1.2 deletion suppressed NSCLC progression and enhanced oxidative stress and significantly decreased the levels of key antioxidant glutathione (GSH) and GCLC, the catalytic subunit of rate-limiting enzyme for GSH synthesis. Moreover, high H1.2 was correlated with the IC50 of multiple chemotherapeutic drugs and with worse prognosis in NSCLC patients receiving chemotherapy; H1.2-deficient NSCLC cells presented reduced survival and increased ROS levels upon cisplatin treatment, while ROS scavenger eliminated the survival inhibition. Mechanistically, H1.2 interacted with NRF2, a master regulator of antioxidative response; H1.2 enhanced the nuclear level and stability of NRF2 and, thus, promoted NRF2 binding to GCLC promoter and the consequent transcription; while NRF2 also transcriptionally up-regulated H1.2. Collectively, these results uncovered a tumor-driving role of H1.2 in NSCLC and indicate an "H1.2-NRF2" antioxidant feedforward cycle that promotes tumor progression and chemoresistance.

Dynamics of Endothelial Cell Generation and Turnover in Arteries During Homeostasis and Diseases.

BACKGROUND: Endothelial cell (EC) generation and turnover by self-proliferation contributes to vascular repair and regeneration. The ability to accurately measure the dynamics of EC generation would advance our understanding of cellular mechanisms of vascular homeostasis and diseases. However, it is currently challenging to evaluate the dynamics of EC generation in large vessels such as arteries because of their infrequent proliferation. METHODS: By using dual recombination systems based on Cre-loxP and Dre-rox, we developed a genetic system for temporally seamless recording of EC proliferation in vivo. We combined genetic recording of EC proliferation with single-cell RNA sequencing and gene knockout to uncover cellular and molecular mechanisms underlying EC generation in arteries during homeostasis and disease. RESULTS: Genetic proliferation tracing reveals that ≈3% of aortic ECs undergo proliferation per month in adult mice during homeostasis. The orientation of aortic EC division is generally parallel to blood flow in the aorta, which is regulated by the mechanosensing protein Piezo1. Single-cell RNA sequencing analysis reveals 4 heterogeneous aortic EC subpopulations with distinct proliferative activity. EC cluster 1 exhibits transit-amplifying cell features with preferential proliferative capacity and enriched expression of stem cell markers such as Sca1 and Sox18. EC proliferation increases in hypertension but decreases in type 2 diabetes, coinciding with changes in the extent of EC cluster 1 proliferation. Combined gene knockout and proliferation tracing reveals that Hippo/vascular endothelial growth factor receptor 2 signaling pathways regulate EC proliferation in large vessels. CONCLUSIONS: Genetic proliferation tracing quantitatively delineates the dynamics of EC generation and turnover, as well as EC division orientation, in large vessels during homeostasis and disease. An EC subpopulation in the aorta exhibits more robust cell proliferation during homeostasis and type 2 diabetes, identifying it as a potential therapeutic target for vascular repair and regeneration.

Soybean type-B response regulator GmRR1 mediates phosphorus uptake and yield by modifying root architecture.

Phosphorus (P) plays a pivotal role in plant growth and development. Low P stress can greatly hamper plant growth. Here, we identified a QTL (named QPH-9-1), which is associated with P efficiency across multiple environments through linkage analysis and genome-wide association study. Furthermore, we successfully cloned the underlying soybean (Glycine max) gene GmRR1 (a soybean type-B Response Regulator 1) that encodes a type-B response regulator protein. Knockout of GmRR1 resulted in a substantial increase in plant height, biomass, P uptake efficiency, and yield-related traits due to the modification of root structure. In contrast, overexpression of GmRR1 in plants resulted in a decrease in these phenotypes. Further analysis revealed that knockout of GmRR1 substantially increased the levels of auxin and ethylene in roots, thereby promoting root hair formation and growth by promoting the formation of root hair primordium and lengthening the root apical meristem. Yeast two-hybrid, bimolecular fluorescence complementation, and dual-luciferase assays demonstrated an interaction between GmRR1 and Histidine-containing Phosphotransmitter protein 1. Expression analysis suggested that these proteins coparticipated in response to low P stress. Analysis of genomic sequences showed that GmRR1 underwent a selection during soybean domestication. Taken together, this study provides further insights into how plants respond to low P stress by modifying root architecture through phytohormone pathways.

ACC SYNTHASE4 inhibits gibberellin biosynthesis and FLOWERING LOCUS T expression during citrus flowering.

Flowering is an essential process in fruit trees. Flower number and timing have a substantial impact on the yield and maturity of fruit. Ethylene and gibberellin (GA) play vital roles in flowering, but the mechanism of coordinated regulation of flowering in woody plants by GA and ethylene is still unclear. In this study, a lemon (Citrus limon L. Burm) 1-aminocyclopropane-1-carboxylic acid synthase gene (CiACS4) was overexpressed in Nicotiana tabacum and resulted in late flowering and increased flower number. Further transformation of citrus revealed that ethylene and starch content increased, and soluble sugar content decreased in 35S:CiACS4 lemon. Inhibition of CiACS4 in lemon resulted in effects opposite to that of 35S:CiACS4 in transgenic plants. Overexpression of the CiACS4-interacting protein ETHYLENE RESPONSE FACTOR3 (CiERF3) in N. tabacum resulted in delayed flowering and more flowers. Further experiments revealed that the CiACS4-CiERF3 complex can bind the promoters of FLOWERING LOCUS T (CiFT) and GOLDEN2-LIKE (CiFE) and suppress their expression. Moreover, overexpression of CiFE in N. tabacum led to early flowering and decreased flowers, and ethylene, starch, and soluble sugar contents were opposite to those in 35S:CiACS4 transgenic plants. Interestingly, CiFE also bound the promoter of CiFT. Additionally, GA3 and 1-aminocyclopropanecarboxylic acid (ACC) treatments delayed flowering in adult citrus, and treatment with GA and ethylene inhibitors increased flower number. ACC treatment also inhibited the expression of CiFT and CiFE. This study provides a theoretical basis for the application of ethylene to regulate flower number and mitigate the impacts of extreme weather on citrus yield due to delayed flowering.

Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress.

ABSTRACT: Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL), but pan-Notch inhibitors showed excessive toxicity in clinical trials. To find alternative ways to target Notch signals, we investigated cell division cycle 73 (Cdc73), which is a Notch cofactor and key component of the RNA polymerase-associated transcriptional machinery, an emerging target in T-ALL. Although we confirmed previous work that CDC73 interacts with NOTCH1, we also found that the interaction in T-ALL was context-dependent and facilitated by the transcription factor ETS1. Using mouse models, we showed that Cdc73 is important for Notch-induced T-cell development and T-ALL maintenance. Mechanistically, chromatin and nascent gene expression profiling showed that Cdc73 intersects with Ets1 and Notch at chromatin within enhancers to activate expression of known T-ALL oncogenes through its enhancer functions. Cdc73 also intersects with these factors within promoters to activate transcription of genes that are important for DNA repair and oxidative phosphorylation through its gene body functions. Consistently, Cdc73 deletion induced DNA damage and apoptosis and impaired mitochondrial function. The CDC73-induced DNA repair expression program co-opted by NOTCH1 is more highly expressed in T-ALL than in any other cancer. These data suggest that Cdc73 might induce a gene expression program that was eventually intersected and hijacked by oncogenic Notch to augment proliferation and mitigate the genotoxic and metabolic stresses of elevated Notch signaling. Our report supports studying factors such as CDC73 that intersect with Notch to derive a basic scientific understanding on how to combat Notch-dependent cancers without directly targeting the Notch complex.

Erythropoietin restrains the inhibitory potential of interneurons in the mouse hippocampus.

Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development.

Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

Surgery-induced renal ischemia and reperfusion (I/R) injury and nephrotoxic drugs like cisplatin can cause acute kidney injury (AKI), for which there is no effective therapy. Lipid accumulation is evident following AKI in renal tubules although the mechanisms and pathological effects are unclear. Here, we report that Ehmt2-encoded histone methyltransferase G9a is upregulated in patients and mouse kidneys after AKI. Renal tubular specific knockout of G9a (Ehmt2Ksp ) or pharmacological inhibition of G9a alleviates lipid accumulation associated with AKI. Mechanistically, G9a suppresses transcription of the lipolytic enzyme Ces1; moreover, G9a and farnesoid X receptor (FXR) competitively bind to the same promoter regions of Ces1. Ces1 is consistently observed to be downregulated in the kidney of AKI patients. Pharmacological inhibition of Ces1 increases lipid accumulation, exacerbates renal I/R-injury and eliminates the beneficial effects on AKI observed in Ehmt2Ksp mice. Furthermore, lipid-lowering atorvastatin and an FXR agonist alleviate AKI by activating Ces1 and reducing renal lipid accumulation. Together, our results reveal a G9a/FXR-Ces1 axis that affects the AKI outcome via regulating renal lipid accumulation.