Biology subjects

Gong, W.

Publications and source records attributed to Gong, W..

At least 19 recordsLinked to original sources

bioRxiv2026

The SWI/SNF subunit SWI3B functions with the m6A writer complex to establish embryo patterning in Arabidopsis

N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotes and is essential for Arabidopsis embryogenesis. However, how m6A mRNA methylation is coordinated with other regulatory pathways during development including embryogenesis remains largely unknown. Here, we report the SWI/SNF chromatin-remodeling subunit SWI3B as a bona fide interactor of the m6A methyltransferase MTA. Like m6A writer mutants, SWI3B is required for early embryo development. We demonstrate that the interaction between MTA and SWI3B is required for MTA function during embryogenesis. MTA and SWI3B are both required to establish the correct expression pattern of WOX8 and proper auxin maxima during early embryogenesis. Transcriptome analysis of isolated embryos from mta, swi3b, and fip37 mutants identified a shared set of upregulated transcripts, including STM as well as several NAC and ERF transcription factors that are normally absent or expressed at very low levels during early embryogenesis. Embryo-specific overexpression of ANAC087 and ERF114 genes phenocopied early embryonic defects observed in mta and swi3b mutants, indicating that their ectopic expression contributes to the observed developmental phenotype. Moreover, SWI3B and MTA are both required for m6A deposition on specific developmental transcripts. Together, our findings uncover a mechanism by which chromatin remodeling and m6A-mediated RNA regulation cooperate to suppress the precocious stability of key developmental regulators, thereby contributing to the establishment of the transcriptional program required for early embryo patterning in Arabidopsis. HighlightsO_LIThe SWI/SNF subunit SWI3B is a functional interactor of the m6A methyltransferase MTA during Arabidopsis embryogenesis C_LIO_LISWI3B and MTA cooperate to establish embryo patterning, WOX8 expression, and auxin maxima C_LIO_LIMTA and SWI3B suppress precocious expression of STM, ANAC087 and ERF114 transcription factors that disrupt early embryo development C_LIO_LISWI3B links chromatin-associated regulation with m6A-mediated control of transcript stability C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=161 HEIGHT=200 SRC="FIGDIR/small/744595v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1056f76org.highwire.dtl.DTLVardef@1d8b9d6org.highwire.dtl.DTLVardef@190918corg.highwire.dtl.DTLVardef@439ce1_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2026

Effects of different shading levels on growth, physiology and leaf surface micromorphology of Sorbus sibirica "Dong Hong" seedlings

BackgroundSorbus sibirica Dong Hong is a promising ornamental cultivar, but its optimal light conditions remain unclear. AimsThis study evaluated the effects of shading on seedling growth, physiology, root morphology, and leaf surface micromorphology. MethodsOne-year-old seedlings were grown under full sunlight (CK) and 30%, 50%, or 70% shade for 100 days. Growth, biomass, root traits, chlorophyll, invertase, soluble protein, stomatal characteristics, and epicuticular wax morphology were determined. ResultsShading significantly affected all measured traits. The 30% shade treatment produced the greatest seedling height, which increased by 118.18% compared with CK, and the highest chlorophyll content, which increased by 120.21%. Soluble protein content was slightly increased, whereas invertase activity decreased under moderate shading. Although total biomass decreased by 18.63%, root development remained relatively stable under 30% shade, with slight increases in total root length and average root diameter. Stomatal density was highest under this treatment, and the epicuticular wax structure remained relatively regular. In contrast, 70% shade markedly inhibited biomass accumulation and root development. ConclusionsModerate shading, particularly 30%, provided the most favorable light environment for Sorbus sibirica Dong Hong seedlings and is recommended for summer nursery cultivation in Northeast China.

plant biology↗

bioRxiv2026

SWI3b restricts AGO5 expression to promote the initiation of megagametogenesis in Arabidopsis

Female germline development is fundamental to plant reproduction. During megasporogenesis, a somatic ovule cell differentiates into a megaspore mother cell (MMC) and undergoes meiosis to produce a single haploid megaspore while three spores degenerate. The surviving functional megaspore undergoes three rounds of mitosis during the process of megagametogenesis to produce the seven-celled female gametophyte or embryo sac. The mechanism by which the functional megaspore initiates gametogenesis remained unclear. Here, we show that the chromatin remodelling protein SWI3b is required for the initiation of megagametogenesis, but not for megasporogenesis. SWI3b activity either in the MMC or somatic ovule primordium cells alone is not sufficient for the initiation of megagametogenesis. We identified AGO5 as a direct target of SWI3b, which restricts AGO5 expression to the nucellus. We further show that SWI3b is required for maintaining low histone H3 lysine 9 acetylation level at the AGO5 locus, while elevated AGO5 abundance in the nucellus disrupts the initiation of megagametogenesis. In summary, our study reveals that SWI3b promotes the initiation of megagametogenesis through chromatin-mediated repression of AGO5, leading to its exclusion from the MMC and thereby linking histone acetylation and epigenetic mechanisms to the development of the female germ cells. HighlightsO_LIThe chromatin remodeling complex component SWI3b is required for the initiation of megagametogenesis and early embryo development. C_LIO_LIIn ovule primordia SWI3b restricts AGO5 expression to the nucellus C_LIO_LISWI3b acts via regulating histone acetylation around the AGO5 transcription start site. C_LIO_LIDevelopment of female germ cells are associated to histone acetylation C_LI

plant biology↗

bioRxiv2026

Microhomology-Mediated Tandem Duplication Drives Tandem Repeat Formation Across Life

Tandem repeats (TR) are common genomic elements that are highly variable and with major functional consequences. Yet, the evolutionary trajectory for their formation remains poorly understood. One proposed mechanism is microhomology-mediated tandem duplication (MTD), in which single-copy DNA segments flanked by microhomology undergo tandem duplication (TD) and can further expand into TRs. Although MTD was first identified in the fission yeast Schizosaccharomyces pombe, its universal occurrence and postulated role in TR evolution have not been established. Using whole-genome deep sequencing and new analytical tools, we show that MTDs occur de novo universally across bacteria, archaea, fungi, and viruses. Further analysis of 2,245 reference genomes and millions of isolate genomes from 103 prokaryotic and eukaryotic microbial species, combined with human population TD data, somatic-germline mutations, and disease-associated variants, reveals that MTDs are consistently the dominant TD-forming mechanism across domains of life. Evidence suggests that MTDs have initiated the formation of the majority of existing TRs in genomes. Importantly, MTDs also prevail in human pathogenic TR mutations, including those linked to cancers. Mechanistically, deletion of the conserved mutator gene Rad27 specifically increased de novo MTD frequency in the budding yeast Saccharomyces cerevisiae, implicating Rad27-mediated Okazaki fragment maturation in MTD formation. These findings establish MTD as a universal and functionally significant mechanism for TR genesis. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/708716v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@db9ff1org.highwire.dtl.DTLVardef@e1a14corg.highwire.dtl.DTLVardef@124be79org.highwire.dtl.DTLVardef@15531ea_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementMicrohomology-mediated tandem duplications (MTDs) represent a universal mechanism driving tandem repeat formation across all domains of life--from viruses to humans. These duplications initiate genome evolution by expanding into functional tandem repeats and are the predominant form of pathogenic tandem duplications in human cancers and heritable disorders. Critically, disruption of the conserved Okazaki fragment processing pathway promotes MTD formation, establishing a fundamental link between DNA replication fidelity and genomic plasticity.

microbiology↗

bioRxiv2026

Unlocking Ultrasensitive Phosphoproteomics of Nanoscale Samples: A Rapid IMAC Enrichment Platform Using Ti-PAN Tip

Protein phosphorylation is a critical mechanism in cellular signal transduction, playing essential roles in various cellular processes. However, significant challenges of their low abundance, high dynamic range, and complexity are especially prominent for accurate phosphoproteome analysis in nanoscale samples, such as oocytes, where misregulation of phosphorylation can lead to infertility. In this study, we developed a novel phosphopeptide enrichment tip (Ti-PAN) using highly hydrophilic textile PAN fibers, enabling rapid in-situ one-tip IMAC enrichment in just 8 minutes. This approach not only minimizes sample loss but also enhances analytical sensitivity and is easily adaptable to automation for high-throughput applications, demonstrating excellent recovery (>94%) and outstanding selectivity for phosphopeptides with remarkable resistance to interference up to 1:5000. By integrating it with a compatible sample preparation workflow based on n-dodecyl {beta}-D-maltoside (DDM) lysis with the high-sensitivity MS data acquisition method of turboDDA, comprehensive mapping of phosphosites in microsamples was achieved, including those from the ERK interactome, mouse brain slices, and oocytes. Using this approach, we identified 2,139 to 11,296 phosphosites across 645 to 2,168 phosphoproteins from samples ranging from 100 to 100,000 cells. Furthermore, we successfully applied this strategy to analyze the phosphoproteome of mouse oocytes at different developmental stages, using as few as 5 oocytes per sample. This led to the identification of 2,709 phosphosites on 701 phosphoproteins, revealing several key kinases involved in meiotic resumption and oocyte maturation, including STK4 (serine/threonine kinase 4) and DYRK3 (dual specificity tyrosine phosphorylation-regulated kinase 3). To our knowledge, this represents the deepest coverage of phosphoproteomes from such minimal oocyte material reported to date, offering valuable mechanistic insights into developmental controls during oocyte maturation. This Ti-PAN-based method provides a robust, versatile, and automatable platform for large-scale, highly sensitive phosphopeptide enrichment, substantially advancing phosphoproteomic studies in complex biological systems.

biochemistry↗

bioRxiv2025

Impact of Absent in Melanoma 2 (AIM2) on Antigen-Specific CD4+ T cell Activation and Homeostasis.

The intrinsic role of Absent in Melanoma 2 (AIM2) in CD4+ T cells during antigen-specific activation and differentiation is not fully understood. To address this, we crossed AIM2-deficient mice with OT-II/RAG transgenic mice, which express an ovalbumin-specific T cell receptor in CD4+ T cells (OT-II). We found that AIM2 does not regulate thymic selection of CD4+ thymocytes, but may promote trafficking or survivability of CD4+ T cells in the spleen. In vitro coculture assays revealed that Aim2-/- OT-II CD4+ T cells produce significantly less IL-2 than wild type OT-II CD4+ T cells when cocultured with ovalbumin-incubated dendritic cells. However, we found no differences in CD4+ T cell proliferative capacity and differentiation among WT OT-II and Aim2-/- OT-II CD4+ T cells following OVA immunization in vivo. Finally, adoptively transferred WT and Aim2-/- OT-II cells controlled the growth of implanted OVA-expressing NOOC2 syngeneic tumors at an equal capacity. Taken together, these results indicate that AIM2 contributes to CD4+ T cell homeostasis in secondary lymphoid organs in vivo. AIM2 also intrinsically promotes IL-2 production in response to antigen-specific activation in vitro. However, this loss of IL-2 does not translate to measurable defects in proliferative, differentiation or effector function during OVA immunization or tumor challenge in vivo.

immunology↗

bioRxiv2025

Adaptive Responses Directed by CREB Control Epithelial-Mesenchymal Plasticity in Cancer

Cellular plasticity plays essential roles in development including organogenesis and tissue homeostasis. The epithelial-to-mesenchymal transition (EMT) is no longer considered a binary switch but rather a dynamic process characterized by a continuum of metastable intermediates having unique features. This epithelial-mesenchymal (E/M) plasticity can be co-opted by cancer cells to promote dedifferentiation that results in hybrid E/M states which increase tumor heterogeneity and generate distinct molecular and phenotypic adaptations that promote drug resistance, dormancy, recurrence, and/or cell invasion and metastasis. The mechanisms that coordinate and maintain metastable hybrid E/M states are poorly understood, and here we report they are controlled by the master transcription factor CREB which regulates adaptive response genes necessary for E/M plasticity. Specifically, a CREB-dependent head and neck cancer model validated the role of CREB in cancer cell plasticity and revealed that it controls a non-canonical EMT gene signature. Moreover, analyses of this signature across cancer types identified the transcriptional regulators VGLL3 and KLF3 as core PanCancer mediators of hybrid E/M states, and gain- and loss-of-function studies established that CREB regulates E/M plasticity by coordinating VGLL3 and KLF3 to drive metastasis.

cell biology↗

bioRxiv2025

A multi-tissue atlas of genetic regulatory effects in sheep

Characterizing the impact of genomic variants on genome function and ultimately complex traits in livestock is essential for the development of sustainable precision agriculture and comparative genomics. Here, as part of the Farm animal Genotype-Tissue Expression (FarmGTEx) project, we present the pilot phase of the SheepGTEx resource through analyzing 6,761 RNA-sequencing samples of 51 primary tissues in a multi-breed population of sheep. We identify millions of regulatory variants associated with seven types of molecular phenotypes, and fine-map 322,468 primary and 114,017 non-primary effects, revealing a high degree of regulatory allelic heterogeneity. We systematically characterize the pleiotropic effects of these variants on molecular phenotypes, assess their context-specific regulatory patterns across tissues, breeds, sexes, and developmental stages, as well as explore their evolutionary constraints across mammals. Finally, we demonstrate the substantial potential of the SheepGTEx resource (https://sheepgtex.farmgtex.org), by providing examples of regulatory mechanisms underpinning 34 complex traits, population divergence between European and Asian breeds, and adaptive evolution in sheep over the past ten millennia.

genomics↗

bioRxiv2025

Pulmonary Vascular Endothelial Dysfunction is Induced by Non-Pulsatile Pulmonary Blood Flow in an Ovine Classic Glenn Model

Structured AbstractO_ST_ABSBackgroundC_ST_ABSPulmonary vascular disease (PVD) in patients with single ventricular heart disease following the partial cavalpulmonary connection (Glenn) is a significant source of morbidity. However, the etiology of pulmonary vascular endothelial cell (EC) dysfunction, an established precursor to PVD, is incompletely understood but may involve abnormal blood flow patterns, hypoxemia, and polycythemia. HypothesisUtilizing an ovine Glenn model, we hypothesized that non-pulsatile pulmonary blood flow (PBF) induces pulmonary vascular EC dysfunction, independent of hypoxemia or polycythemia. MethodsSeven lambs (6-8 weeks old) underwent a Glenn procedure. Eight weeks later, Glenn and age-matched controls were studied. The response to the endothelium-dependent vasodilator acetylcholine (Ach) was determined in isolated pulmonary arteries (PA). Nitric oxide (NO) and endothelin-1 (ET-1) signaling was determined in right lung tissues. Indices of cell proliferation, angiogenesis, and apoptosis were determined in PA endothelial cells (PAECs). Comparisons were made by unpaired t-test and ANOVA. ResultsThere were no differences in age, hemoglobin, or oxygen saturation between groups. Mean PA pressure and left PA flow were higher, and right lung blood flow was lower in Glenn lambs compared to controls (p<0.05). All other baseline hemodynamics were similar. Glenn PAs had impaired relaxation to Ach. Glenn lung NO metabolite levels (NOx) and eNOS protein were lower, and ET-1 levels and prepro-ET-1 protein were higher than controls (p<0.05). Glenn PAECs had higher rates of proliferation and angiogenesis, and decreased apoptosis (p < 0.05). ConclusionsThe initiation of non-pulsatile PBF following the Glenn induces early EC dysfunction independent of hypoxemia and polycythemia.

physiology↗

bioRxiv2025

DAXX governs the silencing of LINE1 during spermatogenesis in mice

The suppression of transposable elements in germline is critical for safeguarding fertility. Here we identify that the DAXX, a potent transcription repressor and an H3.3 chaperone, is indispensable for transposable elements silencing during spermatogenesis. Male mice with conditional knockout of Daxx in germ cells mediated by Ddx4-cre display delayed meiotic progression, deformed and reduced production of sperms, and an age-dependent decline in fertility. The ablation of DAXX results in activation of evolutionarily young LINE1 and ERVs subfamilies. Mechanistically, DAXX interacts with DMAP1 to maintain DNA methylation of LINE1 in meiotic cells. In summary, this study identifies DAXX as a previously unknown regulator of spermatogenesis and demonstrates that it functions as an epigenetic regulator to maintain the silencing the young LINE1 by DNA methylation.

developmental biology↗

bioRxiv2025

Brain Diffusion Transformer for Personalized Neuroscience and Psychiatry

Task-fMRI analyses typically focus on localized activation contrasts between stimuli, neglecting the brains dynamic hierarchy. We introduce Brain Diffusion Transformer (Brain-DiT), a deep generative model capturing recurrent processing underlying individualized neurocognitive state transitions via functional networks. Without prior assumptions, Brain-DiT identifies canonical cognitive regions in the brain and reveals replicable subgroups with distinct neural circuits in large cohorts, offering critical clinical insights overlooked by traditional methods: individuals exhibiting negative emotion bias, linked to language-related regions, had a 12-fold higher likelihood of major depression, and those with maladaptive inhibition strategies, associated with overactive medial frontal regions, showed a 9-fold increased risk of alcohol abuse. By bridging cognitive theory and psychiatric applications, Brain-DiT provides a unified analytical paradigm, paving the way for operational personalized medicine in psychiatry.

neuroscience↗

bioRxiv2025

Uncovering the molecular basis of high morphinan product efficiency in opium poppy through Multi-omics integrated analysis with multi-capsules

Exploring the genetic landscape and corresponding regulatory mechanisms influencing morphine and related alkaloid production efficiency in the opium poppy (Papaver Somniferum L.) is important for sustainable medicinal production. However, information regarding the corresponding medicinal properties of poppy subspecies remains elusive, and the correlation between agronomic traits and morphine production remains unclear. Therefore, this study aims to investigate the distinction between two poppy subspecies: Shan Yang (SY) and Lan Tian (LT). Physiological data revealed that SY exhibited greater tolerance to environmental stress and a higher morphine content than LT, especially during the reproductive stage. To investigate genetic and molecular mechanisms underlying different tolerance traits and morphine synthesis efficiencies, a comprehensive comparison of genomic, transcriptomic, and metabolomic data was conducted, showing significantly higher single nucleotide polymorphism (SNP) frequency in SY (23.78%) compared to LT (23.69%). The proportions of SKIP (Skipped Exon) and MIR (Multi Intron Retention) were higher in SY than in LT. SY showed significantly higher gene expression related to benzylisoquinoline alkaloid synthesis, especially those involved in the steps from 1,2 dehydroreticulinium to morphine, narcotoline and noscapine, compared to LT. The upregulated expression of phenylpropanoid biosynthesis-related genes contributes to its more resistant agronomical traits. It plays a synergistic role in alkaloid production. The higher morphine content in SY resulted from an integrated effect controlled at different levels. Summarily, our findings offer new insights into the molecular mechanisms of morphine synthesis and present valuable gene resources for improving poppy cultivars with higher morphine content.

genomics↗

bioRxiv2025

Presence of Hepatitis B virus infection in colon cancer

Hepatitis B virus (HBV) infection affects [~]300 million people worldwide, which population is at an elevated risk of various cancers, such as gastrointestinal cancer, while the matter behind is largely unclear. In this study, we analyzed 10 colonic specimens from 6 colon cancer patients who were also chronic HBV carriers through Fluorescence-activated Cell Sorting and Immunofluorescence assay to inspect the expression of HBsAg (HBV surface antigen), NTCP (current known cellular receptor of HBV) and CD45 (common marker for immune cells) proteins in single-cell resolution. We found that presence of HBsAg in colonic cells was observed in specimens from all patients, and the proportions of HBV-infected cells were higher in tumors than normal tissues. Strikingly, HBsAg in both immune cells and NTCP-negative cells were also observed in all the patients. In vitro experiments further demonstrated that colonic cells expressing NTCP were indeed highly suspectable to HBV infection. Hence, HBV could infect colonic cells (including immune ones) and may play roles during tumorigenesis in colon cancer.

cancer biology↗

bioRxiv2025

CD45-mediated apoptosis and IL2R downregulation by serine proteases from diarrheagenic bacteria

Most enteropathogens secrete one or more members of the serine protease autotransporters of Enterobacteriaceae (SPATE). We previously demonstrated that SPATE cleaves various O-linked glycoproteins on leukocytes, including the tyrosine phosphatase CD45RO. SPATE impairs leukocyte functions and triggers apoptosis in activated T cells in vitro. Here, we show that SPATE produced by pathogenic E. coli, Shigella, and the mouse pathogen Citrobacter rodentium cleaves not only CD45RO but also CD45 isoforms containing exons A and B. We found that the cleavage of CD45 in primary T cells from both human and murine sources correlated with decreased IL2RA (CD25) surface expression in a concentration-dependent manner. SPATE did not cleave CD25 or affect T cell activation. However, SPATE requires CD45 expression for the depletion of CD25 in activated T cells, as SPATE did not significantly impact CD25 in the Jurkat J45.01 cell line, which lacks CD45. More importantly, we discovered that J45.01 cells resisted SPATE-mediated apoptosis, whereas apoptotic wild-type Jurkat cells exhibited decreased surface expression of CD25. Furthermore, we observed that mice infected with C. rodentium lacking SPATE displayed lower mortality, delayed intestinal colonization, reduced inflammatory cytokines, and decreased leukocyte infiltration in the lamina propria while having a higher number of CD25+ T cells compared to mice infected with wild-type CR or the CR SPATE mutant expressing Crc2 in trans. Our data suggest that SPATE-producing pathogens trigger T-cell apoptosis through CD45 via a mechanism akin to IL2 deprivation, demonstrating that SPATE can act as immunomodulators at various levels of the immune system. SIGNIFICANCEWe have demonstrated for the first time that serine proteases (C2S) from clinically relevant pathogens, such as E. coli pathotypes and Shigella, can cleave leukocyte glycoproteins, including the tyrosine phosphatase CD45, which play crucial roles in cellular and immune functions. In this study, we discovered that C2S induces apoptosis in activated T cells through a previously unknown mechanism resembling IL-2 deprivation, mediated by CD45. Furthermore, we found that C2S is essential for bacterial virulence in vivo. This suggests that pathogens producing C2S may possess previously undescribed immunoregulatory functions that enhance their survival in the host and contribute to the disease process by eliminating T cells through the targeting of CD45 and the IL-2 receptor.

microbiology↗

bioRxiv2025

High-throughput 3D super-resolution imaging in deep tissue

Fluorescence images obtained with optical microscopes intrinsically suffer from blur and noise, which can be partially reversed by the deconvolution process. However, the deconvolution process is ill-conditioned, leading to a trade-off between detail preservation and noise suppression. Here, we develop 3D-FUDIP to fully decouple the deconvolution process into two parts: deblurring and denoising, achieving an 8-fold improvement in spatial resolution. By adopting the Poisson model, which obeys the quantum nature of photons, our 3D-FUDIP can be successfully applied to various noise conditions, especially low-light conditions where the photon number is generally extremely small. The results show that our 3D-FUDIP improves the SNR by up to 6-fold with only a one-fifth photon budget. Besides, 3D-FUDIP boosts the spatial bandwidth product (SBP) by one order of magnitude, allowing more spine details to be resolved within a larger imaging volume. By synergizing deep learning with these advances, we propose 3D-FUDIPn to further improve the imaging resolution. We demonstrate 3D-FUDIPs performance in various imaging systems, including confocal, two-photon, and light-sheet microscopes, showing compatibility and potential applications in biological science.

neuroscience↗

bioRxiv2024

OmiGA: A Toolkit for Ultra-efficient Molecular Trait Analysis in Complex Populations

Molecular quantitative trait loci (molQTL) mapping is one of the most popular approaches to systematically characterize functional impacts of genomic variants, leading to advanced understanding of the regulatory mechanisms underpinning complex traits and diseases. However, when applied to high-throughput molecular phenotypes, the existing molQTL mapping tools often implement simple linear models, overlooking complex inter-individual relatedness, leading to false positives and insufficient statistical power. Here, we introduce the Omics Genetic Analysis toolkit (OmiGA), an ultra-efficient linear mixed model (LMM) based toolkit, for molQTL mapping in populations with complex relatedness. Both computational simulations and real data analyses demonstrated that OmiGA outperformed the existing popular tools regarding molQTL discovery power, fine mapping of causal variants, colocalization of molQTL and trait associations, and computational efficiency. In summary, we recommend OmiGA for molQTL mapping in populations with complex relatedness, for example, those in the Farm animal Genotype-Tissue Expression (FarmGTEx) project and family-based molQTL studies in humans.

bioinformatics↗

bioRxiv2024

SOX2-induced IL-1alpha-mediated immune suppression drives epithelial dysplasia malignant transformation

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1 desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1high myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.

cancer biology↗

bioRxiv2024

C-C bond cleavage and generation in TCA cycle driven by radicals and peroxo-bridge like interaction

Tricarboxylic acid (TCA) cycle is one of the most important and common metabolic pathways in different kingdoms of life, in which citrate synthase catalyzes the first irreversible reaction and the rate-limiting step. Reversed oxidative tricarboxylic acid (roTCA) cycle is a newly discovered autotrophic CO2 fixation pathway based on the reversal of TCA cycle, in which citrate synthase catalyzes the thermodynamically unfavorable citrate cleavage reaction. In this work, we proposed that radicals promote C-C bond cleavage of citrate in roTCA cycle based on series intermediate catalytic state of citrate synthases from Desulfurella acetivoran (DaCS) and Thermosulfidibacter takaii (TtCS) obtained by electron paramagnetic resonance (EPR) and X-ray crystallography. We also proposed that the peroxo-bridge like interaction promotes C-C bond generation between acetyl group and oxaloacetate in citrate synthesis reaction based on intermediate state of human citrate synthase by time-resolved characteristic Raman spectroscopy and X-ray diffraction methods. Results also indicate these mechanisms would be widespread among conserved citrate synthases.

biochemistry↗