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Gao, P.

Publications and source records attributed to Gao, P..

At least 37 records · Page 2Linked to original sources

Deciphering the Sequence Basis and Application of Transcriptional Initiation Regulation in Plant Genomes Through Deep Learning

Transcription initiation is a critical regulatory step in plant gene expression, yet its sequence determinants remain largely elusive. Here we introduce GenoRetriever, an interpretable deep learning model that deciphers the sequence basis of transcriptional initiation regulation across plant genomes. Trained on STRIPE-seq data from 16 soybean tissues and six other crop species, GenoRetriever identifies 27 core sequence motifs that govern transcription start site (TSS) selection and usage. The model predicts TSS locations and usage levels with high accuracy, as validated by in silico motif insertions, saturation mutagenesis, and CRISPR-Cas9 promoter editing. It further reveals that 31.85% of natural variation between wild and domesticated soybean drives shifts in promoter motif usage during domestication, and uncovers lineage-specific motif effects between monocots and dicots. This interpretable model and its user-friendly web server for promoter analysis and design make GenoRetriever both a methodological innovation and practical tool for plant functional genomics and crop improvement.

plant biology↗

Mutations differentially affecting the coronavirus Mac1 ADP-ribose binding and hydrolysis activities indicate that it promotes multiple stages of the viral replication cycle

All coronaviruses (CoVs) encode a conserved macrodomain, termed Mac1, in non-structural protein 3 (nsp3) that binds and hydrolyzes ADP-ribose covalently attached to proteins. Mac1 is a key virulence factor that counters antiviral ADP-ribosyltransferase (PARP) activity. Previously, we found that MHV strain JHM (JHMV) with a mutation in the adenine binding site, JHMV-D1329A, was extremely attenuated in all tested cell types as opposed to JHMV-N1347A, which only has a replication defect in bone-marrow derived macrophages (BMDMs). Interestingly, an N1347A/D1329A double mutant was unrecoverable, indicating an essential role for Mac1 in JHMV infection. We hypothesized that these mutations may impact different stages of the MHV lifecycle. First, to clarify how these mutations affected the biochemical activities of Mac1, we generated Mac1 proteins encoding the same mutations. As expected, the D-A mutation was extremely defective in ADP-ribose binding but maintained enzyme activity. In contrast, we previously found that the N-A mutation had WT levels of ADP-ribose binding but low enzyme activity, confirming that these mutations differentially effect the biochemical functions of Mac1. Following infection, D1329A displayed a large defect in the accumulation of viral RNA compared to WT or N1347A in all cells tested. Alternatively, N1347A infection produced normal levels of viral RNA but produced reduced levels of viral protein in interferon competent bone-marrow derived macrophages (BMDMs). These results suggest that Mac1 ADP-ribose binding and enzymatic activities promote different stages of the viral lifecycle, demonstrating the critical importance of Mac1 for JHMV replication. IMPORTANCEOver the last three decades, coronaviruses have repeatedly demonstrated their potential to become significant veterinary and public health threats. Zoonotic transmission of the myriad known coronavirus strains will remain a concern, regardless of the advances in vaccines and treatment. One difficulty in anticipating the next coronavirus outbreak is their diverse lineage and high propensity for mutation and recombination. The coronavirus macrodomain, Mac1, is conserved amongst all known coronaviruses and is also conserved in the Togaviridae and Hepeviridae families. Mac1 is a key factor in viral replication and pathogenesis, but its role in the replication cycle remains unclear. A deeper investigation of Mac1 function will identify conserved antiviral mechanisms and aid in the development of Mac1 inhibitors that represent a novel strategy for antiviral therapeutics.

microbiology↗

X-ray irradiation hinders flight ability of Cydia pomonella male moths by energy metabolism dysfunction

Flight in insects is essential for behaviors such as courtship, foraging, and migration, with energy metabolism serving as its primary energy source. Previous study indicates that X-ray irradiation, even at optimized doses, compromises the flight capacity of male Cydia pomonella moths utilized in sterile insect technique (SIT) programs. However, the underlying mechanisms of this phenomenon have not been fully understood. In this study, we report that the disruption of energy metabolism processes contributing to the diminished flight capabilities observed in X-ray irradiated sterile C. pomonella moths. Compared to the non-irradiated group, irradiated moths exhibited significantly decreased adenosine triphosphate (ATP) levels. Furthermore, a reduction in the enzymatic activity of key components within carbon metabolism pathways was observed, including citrate synthase (CS) in the tricarboxylic acid cycle (TCA), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), glycerol 3-phosphate dehydrogenase (GPDH) in glycolysis, and 3-Hydroxyl-CoA dehydrogenase (HOAD) in fatty acid metabolism. Transcriptional analysis revealed downregulation of expression of genes associated with energy metabolism in the primary locomotor tissues post-irradiation, specifically those encoding CS (CS2), GAPDH (Gapdh2), GPDH (GPD2), and HOAD (HADHA, HADH1, B0272, HADH2) enzymes. Additionally, exogenous supplementation with decanoic acid and citric acid, the agonist and product of CS respectively, enhanced the TCA cycle, increased energy production, and restored flight capacity in sterile moths. These findings not only confirm that X-ray irradiation disrupts energy metabolism leading to impaired flight, but also offer a potential strategy to overcome this limitation before releasing sterile moths as component of integrated pest management programme using the SIT. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/644052v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@c05e61org.highwire.dtl.DTLVardef@17461d9org.highwire.dtl.DTLVardef@1c41b70org.highwire.dtl.DTLVardef@1e58b48_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG

zoology↗

Succinate dehydrogenase activity supports de novo purine synthesis

The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.

biochemistry↗

China Autism Brain Imaging Consortium: Charting Brain Growth in Chinese Children with Autism

Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition characterized by atypical brain growth. While advances in neuroimaging and openly sharing large-sample datasets such as the Autism Brain Imaging Data Exchange (ABIDE) have improved understanding of ASD, most studies focus on adolescents and adults, with early brain development-critical for diagnosis and intervention-remaining underexplored. Existing research predominantly involves Western samples, offering limited insight and generalizability into non-Caucasian populations. We introduce the China Autism Brain Imaging Consortium (CABIC) (https://php.bdnilab.com/resources/), a grassroots effort by researchers across the country to aggregate previously collected multi-site structural MRI datasets and phenotypic information from 1,451 autistic children and 1,119 typically developing children, covering an age range from early childhood to school age (1.0 - 12.92 years). Here, we present this resource and depict brain growth charts to push forward a more comprehensive understanding of the brain development in Chinese autism children. We constructed brain growth charts that reveal a developmental shift in autistic children, transitioning from early overgrowth to delayed maturation. Regional analyses identified distinct atypical trajectories across specific brain regions. Individual deviation scores quantified inter-subject variability, characterizing the heterogeneity of brain development in ASD. Comparative analyses between CABIC and ABIDE highlighted differences potentially attributable to ethnicity and culture, advancing our understanding of cross-population neurodevelopmental diversity. CABIC MRI datasets will be shared publicly to foster investigation of the potential neural mechanisms underlying ASD in non-Western populations and support efforts toward precision medicine for autistic individuals across diverse backgrounds.

neuroscience↗

TaWUS2D regulates the number of grains per spikelet by enhancing the number of fertile ovaries in Multi-Ovary Wheat

Innovative genetic improvements in the staple crop Triticum aestivum (bread wheat) are urgently needed to address the growing global food security crisis. Here, we report the map-based cloning of TaWUS2D, the gene responsible for the dominant multi-ovary phenotype in wheat. Multi-ovary lines are characterized by the development of three fertile ovaries per floret that results in three grains, as opposed to wildtype single ovary wheat. We used HiFi long-reads to assemble a 14.48 Gbp genome scaffold assembly in the background of mutli-ovary wheat line MOV. Using high-resolution genetic mapping, combined with additional genomic resources, we defined the Mov-1 locus to a 135 Kbp region containing two genes. Using five independent deletion mutants and eight TILLING mutants, we demonstrate that a functional WUSCHEL-like protein, TaWUS2D, is required for the multi-ovary phenotype. TaWUS2D is upregulated in the MOV genetic background. This research lays the groundwork for developing new approaches to improve wheat production potential and sustainability in the face of current and future global food challenges.

plant biology↗

Epigenetic Control of TERRA by FTSJ3 is Critical for Telomerase-Driven Cancers

Telomerase reverse transcriptase (hTERT) overexpression, a hallmark of most cancers, drives tumorigenesis by enabling limitless replicative potential. Direct targeting of hTERT is challenging, necessitating alternative strategies. Through genome-wide synthetic dosage lethality (SDL) screening in cancer models, including patient-derived organoids, we identify FTSJ3, an RNA 2-O-methyltransferase, as a critical vulnerability in hTERT-overexpressing cells. FTSJ3 methylates telomeric repeat-containing RNA (TERRA), a modification essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts this cascade, impairing H3K9 trimethylation, HP1-alpha recruitment, and telomeric heterochromatin maintenance. Notably, this reveals an unexpected dependency on TERRA methylation for telomeric heterochromatin stability in hTERT-driven cancers. Non-malignant cells, lacking telomerase activity and de novo telomere repeat synthesis, are unaffected by FTSJ3 suppression. Our findings establish the FTSJ3/TERRA/SUV39H1 axis as a critical mechanism supporting telomeric heterochromatin stability in hTERT-driven cancers. This telomere-directed epigenetic strategy provides a robust framework for translational therapeutic innovation.

cancer biology↗

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

Nonuple atg8 mutant provides genetic evidence for functional specialization of ATG8 isoforms in Arabidopsis thaliana

Autophagy sustains cellular health by recycling damaged or excess components through autophagosomes. It is mediated by conserved ATG proteins, which coordinate autophagosome biogenesis and selective cargo degradation. Among these, the ubiquitin-like ATG8 protein plays a central role by linking cargo to the growing autophagosomes through interacting with selective autophagy receptors. Unlike most ATG proteins, the ATG8 gene family is significantly expanded in vascular plants, but its functional specialization remains poorly understood. Using transcriptional and translational reporters in Arabidopsis thaliana, we revealed that ATG8 isoforms are differentially expressed across tissues and form distinct autophagosomes within the same cell. To explore ATG8 specialization, we generated the nonuple{Delta} atg8 mutant lacking all nine ATG8 isoforms. The mutant displayed hypersensitivity to carbon and nitrogen starvation, coupled with defects in bulk and selective autophagy as shown by biochemical and ultrastructural analyses. Complementation experiments demonstrated that ATG8A could rescue both carbon and nitrogen starvation phenotypes, whereas ATG8H could only complement carbon starvation. Proximity labeling proteomics further identified isoform-specific interactors under nitrogen starvation, underscoring their functional divergence. These findings provide genetic evidence for functional specialization of ATG8 isoforms in plants and lay the foundation for investigating their roles in diverse cell types and stress conditions.

plant biology↗

In Situ Integration of Porous Polyethylene Nanomembrane with Wound Exudates for Scarless Healing

Achieving scarless wound repair through innovative material designs, such as hydrogels infused with growth factors and cells, has been extensively explored. In this study, we introduce a scarless healing material called pgPE, which is based on a porous and biologically inert ultra-high molecular weight polyethylene (UHMWPE) nanomembrane. This highly flexible nanomembrane conforms closely to the wound site and effectively absorbs wound-associated species into its nanopores, forming pgPE in situ. The resulting pgPE creates an ideal environment that fosters physiological metabolism while acting as a barrier against pathogens. Our findings demonstrate that pgPE facilitates complete skin reconstruction, including the regeneration of hair follicles. Additionally, we characterized the immune microenvironment and hypoxic conditions, revealing that pgPE alleviates hypoxia and modulates immune responses, thereby promoting healing towards a scar-free outcome. The integration of wound-associated species within pgPE has been evidenced through three-dimensional Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) analysis of postmortem samples. This study highlights the potential of personalized solutions that align with physiological systems for enhanced wound healing.

bioengineering↗

Upstream open reading frames buffer translational variability during Drosophila evolution and development

Protein abundance tends to be more evolutionarily conserved than mRNA levels both within and between species, yet the mechanisms underlying this phenomenon remain largely unknown. Upstream open reading frames (uORFs) are widespread cis-regulatory elements in eukaryotic genomes that regulate translation, but it remains unclear whether and how uORFs contribute to stabilizing protein levels. In this study, we performed ribosome translation simulations on mRNA to quantitatively assess the extent to which uORF translation influences the translational variability of downstream coding sequences (CDSs) across varying contexts. Our simulations revealed that uORF translation dampens CDS translational variability, with buffering capacity increasing in proportion to uORF efficiency, length, and number. We then compared the translatomes at different developmental stages of two Drosophila species, demonstrating that uORFs buffer mRNA translation fluctuations during both evolution and development. Experimentally, deleting a uORF in the bicoid (bcd) gene--a prominent example of translational buffering--resulted in extensive changes in gene expression and phenotypes in Drosophila melanogaster. Additionally, we observed uORF-mediated buffering between primates and within human populations. Together, our results reveal a novel regulatory mechanism by which uORFs stabilize gene translation during development and across evolutionary time.

evolutionary biology↗

TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity

Due to the inevitable progression to castration-resistant prostate cancer (CRPC) following treatment with androgen deprivation therapy (ADT), it is essential to develop novel treatment approaches for managing CRPC. Here we showed that metalloproteinase TLL1 was positively associated with prostate cancer aggressiveness. Mechanistically, TLL1 promoted prostate cancer cells migration and metastasis through cleaving latent TGF-{beta}1 to activate TGF-{beta} signaling pathway. Moreover, LINC01179 interacted with Miz1 to attenuate TLL1 expression and LINC01179 impaired prostate cancer cell proliferation and migration ability by suppressing TLL1 expression to deactivate TGF-{beta} signaling activity. Meanwhile, we observed that TLL1 increased the expression of PD-L1 by activating TGF-{beta} signaling pathway and TLL1 depletion enhanced the antitumor efficacy by anti-PD-1 antibody via augmenting the infiltration proportions of CD8+ T cells in tumors. In addition, T cell-specific overexpression of TLL1 disrupted T cell development in the thymus. TLL1 overexpression in T cells accelerated RM-1 prostate tumor growth in mice by decreasing the infiltration of CD8+ T cells into tumors. Collectively, our results revealed that TLL1 may be a potential therapeutic target to alter prostate cancer progression.

cancer biology↗

Single-nucleus multiple-organ chromatin accessibility mapping in the rat

The chromatin accessibility landscape is the basis of cell-specific gene expression. We generated a multiorgan, single-nucleus chromatin accessibility landscape from the model organism Rattus norvegicus. For this single-cell atlas, we constructed 25 libraries via snATAC-seq from nine organs in the rat, with a total of over 110,000 cells. Cell classification integrating gene activity scores with known marker genes identified 77 cell types, which were strongly correlated with those in published mouse single-cell transcriptome atlases. We further investigated the enrichment of cell type- and organ-specific transcription factors (TFs), the dynamics of T-cell developmental trajectories across organs, and the conservation and specificity of gene expression patterns across species. These findings provide a foundation for further investigations of the cell composition and gene regulatory networks throughout the rat body. HighlightsO_LIGeneration of a single-cell atlas of chromatin accessibility in nine organs of the rat C_LIO_LICharacterization of cell type- and organ-specific transcription factors (TFs) C_LIO_LIDynamics of chromatin accessibility in developing T cells revealed by cross-organ analysis C_LIO_LIConservation and specificity of gene expression patterns among humans, mice, and rats revealed by cross-species analysis C_LI

genomics↗

Dissecting the molecular basis of variability for flowering time in Camelina sativa

Camelina sativa is an important polyploid oilseed crop with multiple favorable agronomic traits. Capturing the leaf transcriptome of 48 accessions of C. sativa suggests allelic variation for gene expression levels and notably sub-genome dominance, both of which could provide opportunities for crop improvement. Flowering time (FT) is a crucial factor affecting the overall yield of crops. However, our understanding of the molecular mechanisms underlying FT regulation in C. sativa are still limited, partly due to its complex allohexaploid genome. In this study, weighted gene co-expression network analysis (WGCNA), expression quantitative trait loci (eQTL) analysis and transcriptome-wide association study (TWAS) were employed to explore the FT diversity among 48 C. sativa accessions and dissect the underlying molecular basis. Our results revealed a FT-related co-expressed gene module highly enriched with SOC1s and SOC1-like genes, and identified 10 significant FT-associated single nucleotide polymorphisms (SNPs) defining three haplotype groups; thus providing a molecular basis for future genetic improvements in C. sativa breeding.

plant biology↗

Deciphering gene regulatory programs in mouse embryonic skin through single-cell multiomics analysis

BackgroundCell type-specific transcriptional heterogeneity in embryonic mouse skin is well-documented, but few studies have investigated the regulatory mechanisms. ResultsHere, we present high throughput single-cell chromatin accessibility and transcriptome sequencing (HT-scCAT-seq), a method that simultaneously profiles transcriptome and chromatin accessibility. We utilized HT-scCAT-seq to dissect the gene regulatory mechanism governing epidermal stratification, periderm terminal differentiation, and fibroblast specification. ConclusionsBy linking chromatin accessibility to gene expression, we identified candidate cis-regulatory elements (cCREs) and target genes crucial for dermal and epidermal development. We described cells with similar gene expression profiles that exhibit distinct chromatin accessibility statuses during periderm terminal differentiation. Finally, we characterized the underlying lineage-determining transcription factors (TFs), and demonstrated that ALX4 and RUNX2 were candidate TF regulators of the dermal papilla lineage development through in silico perturbation analysis.

developmental biology↗

Cross-species interactome analysis uncovers a conserved selective autophagy mechanism for protein quality control in plants

Selective autophagy is a fundamental protein quality control pathway that safeguards proteostasis by degrading damaged or surplus cellular components, particularly under stress. This process is orchestrated by selective autophagy receptors (SARs) that direct specific cargo for degradation. While significant strides have been made in understanding the molecular framework of selective autophagy, the diversity of SAR repertoires across species remain largely unexplored. Through a comparative interactome analysis across five model organisms, we identified a suite of conserved and lineage-specific SAR candidates. Among these, we validated CESAR as a conserved SAR critical for proteostasis under heat stress. CESAR specifically facilitates the degradation of hydrophobic, ubiquitinated protein aggregates and is indispensable for heat stress tolerance. Our study offers a rich resource for SAR discovery and positions CESAR as a pivotal regulator of proteostasis, with broad implications for improving stress resilience in plants.

plant biology↗

Evolution of the Spatial transcriptomic landscape during the progression of high-grade pancreatic intraductal papillary mucinous neoplasms to invasive cancer

Intraductal papillary mucinous neoplasms (IPMN) is one of the known precancerous lesions. Patients prognosis is aggravated as IPMN transforms into invasive Pancreatic Ductal Adenocarcinoma (PDAC). The molecular mechanisms underlying this progression lack effective experimental models and urgently need to be elaborated. We performed spatial transcriptomics (ST) on fresh tissue samples from the same patient including normal pancreas, high-grade IPMN, and invasive PDAC, and described the step-by-step development of transcriptional landscape including clone evolution and adjacent TME feature variation. Our findings identified the master transcript factors and critical signaling pathways promoting IPMN progression to invasive PDAC. Additionally, both IPMN and PDAC harbored the ELF3, MYC, and KLF4 amplification. The Spatial CNV profile demonstrated significant heterogeneity among PDAC in their spatial distribution compared to IPMN, with seven distinct subclones showing diverse functions, such as hypoxia, oxidative phosphorylation, and epithelial-mesenchymal Transition. We observed a marked shift in the immune landscape, with the depletion of CD4+ T-cells and dendritic cells and an increase in immune-suppressive M2 macrophages in invasive PDAC, indicating a transition to an immune-evasive microenvironment. Additionally, cancer-associated fibroblasts (CAFs), particularly myofibroblastic CAFs, were enriched adjacent to invasive PDAC, suggesting their active role in tumor progression. By leveraging spatial transcriptomic analysis, our study provides comprehensive insights into the intricate molecular landscape that underlies the progression of IPMNs to invasive PDAC. These findings not only enhance our understanding of this complex process but also offer valuable knowledge for early diagnosis and intervention. HighlightsO_LISpatial CNV analysis reveals clonal evolution and distinct subclones in PDAC. C_LIO_LIKey drivers like ELF3, MYC, and KLF4 are amplified in both IPMN and invasive PDAC. C_LIO_LIImmune landscape shifts from pro-inflammatory in IPMN to immune-evasive in PDAC. C_LIO_LIEnrichment of myofibroblastic CAFs suggests their role in tumor progression C_LI

cancer biology↗

AmygdalaGo-BOLT3D: A boundary learning transformer for tracing human amygdala

Each year, thousands of brain MRI scans are collected to study structural development in children and adolescents. However, the amygdala, a particularly small and complex structure, remains difficult to segment reliably, especially in developing populations where its volume is even smaller. To address this challenge, we developed AmygdalaGo-BOLT, a boundary-aware deep learning model tailored for human amygdala segmentation. It was trained and validated using 854 manually labeled scans from pediatric datasets, with independent samples used to ensure performance generalizability. The model integrates multiscale image features, spatial priors, and self-attention mechanisms within a compact encoder-decoder architecture to enhance boundary detection. Validation across multiple imaging centers and age groups shows that AmygdalaGo-BOLT closely matches expert manual labels, improves processing efficiency, and outperforms existing tools in accuracy. This enables robust and scalable analysis of amygdala morphology in developmental neuroimaging studies where manual tracing is impractical. To support open and reproducible science, we publicly release both the labeled datasets and the full source code. TeaserAn AI model enables accurate amygdala segmentation across ages and centers, supporting large-scale brain imaging studies.

neuroscience↗