Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters.

Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.

DNA topology regulates PAM-Cas9 interaction and DNA unwinding to enable near-PAMless cleavage by thermophilic Cas9.

CRISPR-Cas9-mediated genome editing depends on PAM recognition to initiate DNA unwinding. PAM mutations can abolish Cas9 binding and prohibit editing. Here, we identified a Cas9 from the thermophile Alicyclobacillus tengchongensis for which the PAM interaction can be robustly regulated by DNA topology. AtCas9 has a relaxed PAM of N4CNNN and N4RNNA (R = A/G) and is able to bind but not cleave targets with mutated PAMs. When PAM-mutated DNA was in underwound topology, AtCas9 exhibited enhanced binding affinity and high cleavage activity. Mechanistically, AtCas9 has a unique loop motif, which docked into the DNA major groove, and this interaction can be regulated by DNA topology. More importantly, AtCas9 showed near-PAMless editing of supercoiled plasmid in E. coli. In mammalian cells, AtCas9 exhibited broad PAM preference to edit plasmid with up to 72% efficiency and effective base editing at four endogenous loci, representing a potentially powerful tool for near-PAMless editing.

State-dependent architecture of thalamic reticular subnetworks.

Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function. PAPERFLICK:

The whisking oscillator circuit.

Central oscillators are primordial neural circuits that generate and control rhythmic movements1,2. Mechanistic understanding of these circuits requires genetic identification of the oscillator neurons and their synaptic connections to enable targeted electrophysiological recording and causal manipulation during behaviours. However, such targeting remains a challenge with mammalian systems. Here we delimit the oscillator circuit that drives rhythmic whisking-a motor action that is central to foraging and active sensing in rodents3,4. We found that the whisking oscillator consists of parvalbumin-expressing inhibitory neurons located in the vibrissa intermediate reticular nucleus (vIRtPV) in the brainstem. vIRtPV neurons receive descending excitatory inputs and form recurrent inhibitory connections among themselves. Silencing vIRtPV neurons eliminated rhythmic whisking and resulted in sustained vibrissae protraction. In vivo recording of opto-tagged vIRtPV neurons in awake mice showed that these cells spike tonically when animals are at rest, and transition to rhythmic bursting at the onset of whisking, suggesting that rhythm generation is probably the result of network dynamics, as opposed to intrinsic cellular properties. Notably, ablating inhibitory synaptic inputs to vIRtPV neurons quenched their rhythmic bursting, impaired the tonic-to-bursting transition and abolished regular whisking. Thus, the whisking oscillator is an all-inhibitory network and recurrent synaptic inhibition has a key role in its rhythmogenesis.

Arctic amplification-induced decline in West and South Asia dust warrants stronger antidesertification toward carbon neutrality.

Dust loading in West and South Asia has been a major environmental issue due to its negative effects on air quality, food security, energy supply and public health, as well as on regional and global weather and climate. Yet a robust understanding of its recent changes and future projection remains unclear. On the basis of several high-quality remote sensing products, we detect a consistently decreasing trend of dust loading in West and South Asia over the last two decades. In contrast to previous studies emphasizing the role of local land use changes, here, we attribute the regional dust decline to the continuous intensification of Arctic amplification driven by anthropogenic global warming. Arctic amplification results in anomalous mid-latitude atmospheric circulation, particularly a deepened trough stretching from West Siberia to Northeast India, which inhibits both dust emissions and their downstream transports. Large ensemble climate model simulations further support the dominant role of greenhouse gases induced Arctic amplification in modulating dust loading over West and South Asia. Future projections under different emission scenarios imply potential adverse effects of carbon neutrality in leading to higher regional dust loading and thus highlight the importance of stronger anti-desertification counter-actions such as reforestation and irrigation management.

Development of a breast cancer prognostic model based on vesicle-mediated transport-related genes to predict immune landscape and clinical drug therapy.

BACKGROUND: Vesicle-mediated transport, vital for substance exchange and intercellular communication, is linked to tumor initiation and progression. This work was designed to study the role of vesicle-mediated transport-related genes (VMTRGs) in breast cancer (BC)prognosis. METHODS: Univariate Cox analysis was utilized to screen prognosis-related VMTRGs. BC samples underwent unsupervised clustering based on VMTRGs to analyze survival, clinical factors, and immune cell abundance across different subtypes. We constructed a risk model using univariate Cox and LASSO regression analysis, with validation conducted using GEO datasets. Subsequently, we performed tumor mutational burden analysis, and immune landscape analysis on both groups. Ultimately, we conducted immunophenoscore (IPS) scoring to forecast immunotherapy and performed drug sensitivity analysis. RESULTS: We identified 102 VMTRGs associated with BC prognosis. Using these 102 VMTRGs, BC patients were classified into 3 subtypes, with Cluster3 patients showing significantly better survival rates. We constructed a prognostic model for BC based on 12 VMTRGs that effectively predicted patient survival. Riskscore was an independent prognostic factor for BC patients. According to median risk score, high-risk group (HRG) had higher TMB values. The immune landscape of the HRG exhibited characteristics of cold tumor, with higher immune checkpoint expression levels and lower IPS scores, whereas Gemcitabine, Nilotinib, and Oxaliplatin were more suitable for treating low-risk group. CONCLUSION: We classified BC subtypes and built a prognostic model based on VMTRGs. The genes in the prognostic model may serve as potential targets for BC therapy.

HYENA detects oncogenes activated by distal enhancers in cancer.

Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm 'HYENA' to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.

Inhibition of AIM2 inflammasome activation by SOX/ORF37 promotes lytic replication of Kaposi's sarcoma-associated herpesvirus.

Inflammasomes are one kind of important innate immune defense against viral and bacterial infections. Several inflammasome-forming sensors detect molecular patterns of invading pathogens and then trigger inflammasome activation and/or pyroptosis in infected cells, and viruses employ unique strategies to hijack or subvert inflammasome activation. Infection with herpesviruses induces the activation of diverse inflammasomes, including AIM2 and IFI16 inflammasomes; however, how Kaposi's sarcoma-associated herpesvirus (KSHV) counteracts inflammasome activation largely remains unclear. Here, we reveal that the KSHV ORF37-encoded SOX protein suppresses AIM2 inflammasome activation independent of its viral DNA exonuclease activity and host mRNA turnover. SOX interacts with the AIM2 HIN domain through the C-terminal Motif VII region and disrupts AIM2:dsDNA polymerization and ASC recruitment and oligomerization. The Y443A or F444A mutation of SOX abolishes the inhibition of AIM2 inflammasome without disrupting SOX nuclease activity, and a short SOX peptide is capable of inhibiting AIM2 inflammasome activation; consequently, infection with SOX-null, Y443A, or F444A Bac16 recombinant viruses results in robust inflammasome activation, suppressed lytic replication, and increased pyroptosis in human lymphatic endothelial cells in an AIM2-dependent manner. These results reveal that KSHV SOX suppresses AIM2 inflammasome activation to promote KSHV lytic replication and inhibit pyroptosis, representing a unique mechanism for evasion of inflammasome activation during KSHV lytic cycle.

Longitudinal mapping of the development of cortical thickness and surface area in rhesus macaques during the first three years.

Studying dynamic spatiotemporal patterns of early brain development in macaque monkeys is critical for understanding the cortical organization and evolution in humans, given the phylogenetic closeness between humans and macaques. However, due to huge challenges in the analysis of early brain Magnetic Resonance Imaging (MRI) data typically with extremely low contrast and dynamic imaging appearances, our knowledge of the early macaque cortical development remains scarce. To fill this critical gap, this paper characterizes the early developmental patterns of cortical thickness and surface area in rhesus macaques by leveraging advanced computing tools tailored for early developing brains based on a densely sampled longitudinal dataset with 140 rhesus macaque MRI scans seamlessly covering from birth to 36 mo of age. The average cortical thickness exhibits an inverted U-shaped trajectory with peak thickness at around 4.3 mo of age, which is remarkably in line with the age of peak thickness at 14 mo in humans, considering the around 3:1 age ratio of human to macaque. The total cortical surface area in macaques increases monotonically but with relatively lower expansions than in humans. The spatial distributions of thicker and thinner regions are quite consistent during development, with gyri having a thicker cortex than sulci. By 4 mo of age, over 81% of cortical vertices have reached their peaks in thickness, except for the insula and medial temporal cortices, while most cortical vertices keep expanding in surface area, except for the occipital cortex. These findings provide important insights into early brain development and evolution in primates.

Large-scale climate patterns offer preseasonal hints on the co-occurrence of heat wave and O3 pollution in China.

Heat waves and air pollution extremes exert compounding effects on human health and food security and may worsen under future climate change. On the basis of reconstructed daily O3 levels in China and meteorological reanalysis, we found that the interannual variability of the frequency of summertime co-occurrence of heat wave and O3 pollution in China is regulated mainly by a combination of springtime warming in the western Pacific Ocean, western Indian Ocean, and Ross Sea. These sea surface temperature anomalies impose influences on precipitation, radiation, etc., to modulate the co-occurrence, which were also confirmed with coupled chemistry-climate numerical experiments. We thus built a multivariable regression model to predict co-occurrence a season in advance, and correlation coefficient could reach 0.81 (P < 0.01) for the North China Plain. Our results provide useful information for the government to take actions in advance to mitigate damage from these synergistic costressors.

A flexible summary statistics-based colocalization method with application to the mucin cystic fibrosis lung disease modifier locus.

Mucus obstruction is a central feature in the cystic fibrosis (CF) airways. A genome-wide association study (GWAS) of lung disease by the CF Gene Modifier Consortium (CFGMC) identified a significant locus containing two mucin genes, MUC20 and MUC4. Expression quantitative trait locus (eQTL) analysis using human nasal epithelia (HNE) from 94 CF-affected Canadians in the CFGMC demonstrated MUC4 eQTLs that mirrored the lung association pattern in the region, suggesting that MUC4 expression may mediate CF lung disease. Complications arose, however, with colocalization testing using existing methods: the locus is complex and the associated SNPs span a 0.2 Mb region with high linkage disequilibrium (LD) and evidence of allelic heterogeneity. We previously developed the Simple Sum (SS), a powerful colocalization test in regions with allelic heterogeneity, but SS assumed eQTLs to be present to achieve type I error control. Here we propose a two-stage SS (SS2) colocalization test that avoids a priori eQTL assumptions, accounts for multiple hypothesis testing and the composite null hypothesis, and enables meta-analysis. We compare SS2 to published approaches through simulation and demonstrate type I error control for all settings with the greatest power in the presence of high LD and allelic heterogeneity. Applying SS2 to the MUC20/MUC4 CF lung disease locus with eQTLs from CF HNE revealed significant colocalization with MUC4 (p = 1.31 × 10-5) rather than with MUC20. The SS2 is a powerful method to inform the responsible gene(s) at a locus and guide future functional studies. SS2 has been implemented in the application LocusFocus.

BloodNet: An attention-based deep network for accurate, efficient, and costless bloodstain time since deposition inference.

The time since deposition (TSD) of a bloodstain, i.e., the time of a bloodstain formation is an essential piece of biological evidence in crime scene investigation. The practical usage of some existing microscopic methods (e.g., spectroscopy or RNA analysis technology) is limited, as their performance strongly relies on high-end instrumentation and/or rigorous laboratory conditions. This paper presents a practically applicable deep learning-based method (i.e., BloodNet) for efficient, accurate, and costless TSD inference from a macroscopic view, i.e., by using easily accessible bloodstain photos. To this end, we established a benchmark database containing around 50,000 photos of bloodstains with varying TSDs. Capitalizing on such a large-scale database, BloodNet adopted attention mechanisms to learn from relatively high-resolution input images the localized fine-grained feature representations that were highly discriminative between different TSD periods. Also, the visual analysis of the learned deep networks based on the Smooth Grad-CAM tool demonstrated that our BloodNet can stably capture the unique local patterns of bloodstains with specific TSDs, suggesting the efficacy of the utilized attention mechanism in learning fine-grained representations for TSD inference. As a paired study for BloodNet, we further conducted a microscopic analysis using Raman spectroscopic data and a machine learning method based on Bayesian optimization. Although the experimental results show that such a new microscopic-level approach outperformed the state-of-the-art by a large margin, its inference accuracy is significantly lower than BloodNet, which further justifies the efficacy of deep learning techniques in the challenging task of bloodstain TSD inference. Our code is publically accessible via https://github.com/shenxiaochenn/BloodNet. Our datasets and pre-trained models can be freely accessed via https://figshare.com/articles/dataset/21291825.

Suppression of KSHV lytic replication and primary effusion lymphoma by selective RNF5 inhibition.

Primary effusion lymphoma (PEL), a rare aggressive B-cell lymphoma in immunosuppressed patients, is etiologically associated with oncogenic γ-herpesvirus infection. Chemotherapy is commonly used to treat PEL but usually results in poor prognosis and survival; thus, novel therapies and drug development are urgently needed for PEL treatment. Here, we demonstrated that inhibition of Ring finger protein 5 (RNF5), an ER-localized E3 ligase, suppresses multiple cellular pathways and lytic replication of Kaposi sarcoma-associated herpesvirus (KSHV) in PEL cells. RNF5 interacts with and induces Ephrin receptors A3 (EphA3) and EphA4 ubiquitination and degradation. RNF5 inhibition increases the levels of EphA3 and EphA4, thereby reducing ERK and Akt activation and KSHV lytic replication. RNF5 inhibition decreased PEL xenograft tumor growth and downregulated viral gene expression, cell cycle gene expression, and hedgehog signaling in xenograft tumors. Our study suggests that RNF5 plays the critical roles in KSHV lytic infection and tumorigenesis of primary effusion lymphoma.

The U1 small nuclear RNA enhances drought tolerance in Arabidopsis.

Alternative splicing (AS) is an important post-transcriptional regulatory mechanism that improves plant tolerance to drought stress by modulating gene expression and generating proteome diversity. The interaction between the 5' end of U1 small nuclear RNA (U1 snRNA) and the conserved 5' splice site of precursor messenger RNA (pre-mRNA) is pivotal for U1 snRNP involvement in AS. However, the roles of U1 snRNA in drought stress responses remain unclear. This study provides a comprehensive analysis of AtU1 snRNA in Arabidopsis (Arabidopsis thaliana), revealing its high conservation at the 5' end and a distinctive four-leaf clover structure. AtU1 snRNA is localized in the nucleus and expressed in various tissues, with prominent expression in young floral buds, flowers, and siliques. Overexpression of AtU1 snRNA confers enhanced abiotic stress tolerance, as evidenced in seedlings by longer seedling primary root length, increased fresh weight, and a higher greening rate compared to the wild type. Mature AtU1 snRNA overexpressor plants exhibit higher survival rates and lower water loss rates under drought stress, accompanied by a significant decrease in H2O2 and increase in proline. This study also provides evidence of altered expression levels of drought-related genes in AtU1 snRNA overexpressor or genome-edited lines, reinforcing the crucial role of AtU1 snRNA in drought stress responses. Furthermore, the overexpression of AtU1 snRNA influences the splicing of downstream target genes, with a notable impact on SPEECHLESS (SPCH), a gene associated with stomatal development, potentially explaining the observed decrease in stomatal aperture and density. These findings elucidate the critical role of U1 snRNA as an AS regulator in enhancing drought stress tolerance in plants, contributing to a deeper understanding of the AS pathway in drought tolerance and increasing awareness of the molecular network governing drought tolerance in plants.

Dephosphorylation of T517 on Hemocyanin Is Required for Antibacterial Activity in Penaeus vannamei.

Posttranslational modifications expand the functions of immune-related proteins, especially during infections. The respiratory glycoprotein, hemocyanin, has been implicated in many other functions, but the role of phosphorylation modification in its functional diversity is not fully understood. In this study, we show that Penaeus vannamei hemocyanin (PvHMC) undergoes phosphorylation modification during bacterial infection. Dephosphorylation of PvHMC mediated by P. vannamei protein phosphatase 2A catalytic increases its in vitro antibacterial activity, whereas phosphorylation by P. vannamei casein kinase 2 catalytic subunit α decreases its oxygen-carrying capacity and attenuates its in vitro antibacterial activity. Mechanistically, we show that Thr517 is a critical phosphorylation modification site on PvHMC to modulate its functions, which when mutated attenuates the action of P. vannamei casein kinase 2 catalytic subunit α and P. vannamei protein phosphatase 2A catalytic, and hence abolishes the antibacterial activity of PvHMC. Our results reveal that phosphorylation of PvHMC modulates its antimicrobial functions in penaeid shrimp.

ACFIS 2.0: an improved web-server for fragment-based drug discovery via a dynamic screening strategy.

Drug discovery, which plays a vital role in maintaining human health, is a persistent challenge. Fragment-based drug discovery (FBDD) is one of the strategies for the discovery of novel candidate compounds. Computational tools in FBDD could help to identify potential drug leads in a cost-efficient and time-saving manner. The Auto Core Fragment in silico Screening (ACFIS) server is a well-established and effective online tool for FBDD. However, the accurate prediction of protein-fragment binding mode and affinity is still a major challenge for FBDD due to weak binding affinity. Here, we present an updated version (ACFIS 2.0), that incorporates a dynamic fragment growing strategy to consider protein flexibility. The major improvements of ACFIS 2.0 include (i) increased accuracy of hit compound identification (from 75.4% to 88.5% using the same test set), (ii) improved rationality of the protein-fragment binding mode, (iii) increased structural diversity due to expanded fragment libraries and (iv) inclusion of more comprehensive functionality for predicting molecular properties. Three successful cases of drug lead discovery using ACFIS 2.0 are described, including drugs leads to treat Parkinson's disease, cancer, and major depressive disorder. These cases demonstrate the utility of this web-based server. ACFIS 2.0 is freely available at http://chemyang.ccnu.edu.cn/ccb/server/ACFIS2/.

SEdb 2.0: a comprehensive super-enhancer database of human and mouse.

Super-enhancers (SEs) are cell-specific DNA cis-regulatory elements that can supervise the transcriptional regulation processes of downstream genes. SEdb 2.0 (http://www.licpathway.net/sedb) aims to provide a comprehensive SE resource and annotate their potential roles in gene transcriptions. Compared with SEdb 1.0, we have made the following improvements: (i) Newly added the mouse SEs and expanded the scale of human SEs. SEdb 2.0 contained 1 167 518 SEs from 1739 human H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) samples and 550 226 SEs from 931 mouse H3K27ac ChIP-seq samples, which was five times that of SEdb 1.0. (ii) Newly added transcription factor binding sites (TFBSs) in SEs identified by TF motifs and TF ChIP-seq data. (iii) Added comprehensive (epi)genetic annotations of SEs, including chromatin accessibility regions, methylation sites, chromatin interaction regions and topologically associating domains (TADs). (iv) Newly embedded and updated search and analysis tools, including 'Search SE by TF-based', 'Differential-Overlapping-SE analysis' and 'SE-based TF-Gene analysis'. (v) Newly provided quality control (QC) metrics for ChIP-seq processing. In summary, SEdb 2.0 is a comprehensive update of SEdb 1.0, which curates more SEs and annotation information than SEdb 1.0. SEdb 2.0 provides a friendly platform for researchers to more comprehensively clarify the important role of SEs in the biological process.

Annotation and evaluation of base editing outcomes in multiple cell types using CRISPRbase.

CRISPR-Cas base editing (BE) system is a powerful tool to expand the scope and efficiency of genome editing with single-nucleotide resolution. The editing efficiency, product purity, and off-target effect differ among various BE systems. Herein, we developed CRISPRbase (http://crisprbase.maolab.org), by integrating 1 252 935 records of base editing outcomes in more than 50 cell types from 17 species. CRISPRbase helps to evaluate the putative editing precision of different BE systems by integrating multiple annotations, functional predictions and a blasting system for single-guide RNA sequences. We systematically assessed the editing window, editing efficiency and product purity of various BE systems. Intensive efforts were focused on increasing the editing efficiency and product purity of base editors since the byproduct could be detrimental in certain applications. Remarkably, more than half of cancer-related off-target mutations were non-synonymous and extremely damaging to protein functions in most common tumor types. Luckily, most of these cancer-related mutations were passenger mutations (4840/5703, 84.87%) rather than cancer driver mutations (863/5703, 15.13%), indicating a weak effect of off-target mutations on carcinogenesis. In summary, CRISPRbase is a powerful and convenient tool to study the outcomes of different base editors and help researchers choose appropriate BE designs for functional studies.

Mapping developmental regionalization and patterns of cortical surface area from 29 post-menstrual weeks to 2 years of age.

Surface area of the human cerebral cortex expands extremely dynamically and regionally heterogeneously from the third trimester of pregnancy to 2 y of age, reflecting the spatial heterogeneity of the underlying microstructural and functional development of the cerebral cortex. However, little is known about the developmental patterns and regionalization of cortical surface area during this critical stage, due to the lack of high-quality imaging data and accurate computational tools for pediatric brain MRI data. To fill this critical knowledge gap, by leveraging 1,037 high-quality MRI scans with the age between 29 post-menstrual weeks and 24 mo from 735 pediatric subjects in two complementary datasets, i.e., the Baby Connectome Project (BCP) and the developing Human Connectome Project (dHCP), and state-of-the-art dedicated image-processing tools, we unprecedentedly parcellate the cerebral cortex into a set of distinct subdivisions purely according to the developmental patterns of the cortical surface. Our discovered developmentally distinct subdivisions correspond well to structurally and functionally meaningful regions and reveal spatially contiguous, hierarchical, and bilaterally symmetric patterns of early cortical surface expansion. We also show that high-order association subdivisions, where cortical folds emerge later during prenatal stages, undergo more dramatic cortical surface expansion during infancy, compared with the central regions, especially the sensorimotor and insula cortices, thus forming a distinct central-pole division in early cortical surface expansion. These results provide an important reference for exploring and understanding dynamic early brain development in health and disease.

Electron delocalization triggers nonradical Fenton-like catalysis over spinel oxides.

Nonradical Fenton-like catalysis offers opportunities to overcome the low efficiency and secondary pollution limitations of existing advanced oxidation decontamination technologies, but realizing this on transition metal spinel oxide catalysts remains challenging due to insufficient understanding of their catalytic mechanisms. Here, we explore the origins of catalytic selectivity of Fe-Mn spinel oxide and identify electron delocalization of the surface metal active site as the key driver of its nonradical catalysis. Through fine-tuning the crystal geometry to trigger Fe-Mn superexchange interaction at the spinel octahedra, ZnFeMnO4 with high-degree electron delocalization of the Mn-O unit was created to enable near 100% nonradical activation of peroxymonosulfate (PMS) at unprecedented utilization efficiency. The resulting surface-bound PMS* complex can efficiently oxidize electron-rich pollutants with extraordinary degradation activity, selectivity, and good environmental robustness to favor water decontamination applications. Our work provides a molecule-level understanding of the catalytic selectivity and bimetallic interactions of Fe-Mn spinel oxides, which may guide the design of low-cost spinel oxides for more selective and efficient decontamination applications.