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Zhou, Y.

Publications and source records attributed to Zhou, Y..

At least 109 records · Page 6Linked to original sources

From Spectra to Digital Phenotypes: Wearable Multispectral Sensing for Precision Light and Green Space Exposure

Light is a modifiable determinant of health, yet real-world exposure assessment is often reduced to illuminance alone, lacks environmental context, or relies on privacy-sensitive sensing. We present SpectraVita, a low-cost, compact multispectral wearable that continuously samples 11 ultraviolet-to-near-infrared bands and, through a privacy-preserving pipeline without cameras or location tracking, produces interpretable digital phenotypes of lighting environment (natural vs. artificial and source type) and vegetation context alongside standard visual and non-visual light metrics. In extensive in-the-wild recordings spanning diverse scenes, times of day, weather conditions, and light sources, we observe distinctive spectral signatures that enable supervised models to achieve a macro-averaged F1 score of 0.988{+/-}0.004 for light-source classification and green-space detection in boundary-free environments. A sensor-derived normalized difference vegetation index (NDVI) emerges as an explainable, physically grounded marker linking natural light exposure and greenness. Robustness is supported by scenario-shift testing, image-segmentation validation, and mixed-environment experiments that demonstrate sensitivity to partial and transient exposures, as well as by longitudinal stationary monitoring and deployment in a cohort of thousands of participants capturing seasonal and behavioral variability. SpectraVita enables individualized, privacy-preserving, longitudinal monitoring of light and greenness exposure at scale, addressing a key measurement gap for precision and population health studies of daily photic environments.

bioengineering↗

GABA antagonises ABA perception and signalling in plants

Abscisic acid (ABA) is a central regulator of plant growth and stress responses. However, it also negatively impact germination, growth, and reproductive performance, highlighting the need for mechanisms that fine-tune its signalling. Here, we identify {gamma}-aminobutyric acid (GABA) as an endogenous antagonist of plant ABA receptor. We show that GABA binds the clade A protein phosphatase-ABI1, disrupting its association with the ABA receptor PYL1, blocking ABA binding, thereby attenuating ABA signalling. GABA modulates ABA-control of stomatal aperture and seed germination, demonstrating its broad physiological influence. Notably, GABA accumulation during stress coincides with the subsequent decline in ABA, consistent with a delayed feedback signal of ABA activity. Together, this work identifies GABA as an antagonist of ABA and provides a mechanism balancing plant stress resilience and growth.

plant biology↗

Somatic-to-germline transmission of horizontally acquired extrachromosomal circular DNA in Brassica graft chimeras

Whether somatically acquired traits can contribute to heritable variation has remained an open question in plant biology for over a century. Here, using graft-induced periclinal chimeras between Brassica juncea and Brassica oleracea, we identified extrachromosomal circular DNA (eccDNA) as mobile genetic elements capable of crossing histological boundaries and entering the germline. We demonstrated that grafting could promote the horizontal transfer of eccDNA between somatic cell layers, enabling its stable maintenance in recipient tissues and permitting transmission through sexual reproduction across multiple generations. We found that transmitted eccDNA is non-randomly distributed across the genome, preferentially originating from gene-dense regions, and enriched for features associated with molecular persistence, such as inverted repeats, hairpin-forming sequences, and autonomously replicating sequence (ARS) consensus motifs. These genetic regions conferred replication competence, as evidenced by autonomous propagation in an ARS-less heterologous yeast system. Sexual progeny carrying graft-acquired eccDNA exhibited reproducible and lineage-dependent alterations in leaf morphology and drought tolerance, accompanied by coordinated transcriptional reprogramming. Notably, a subset of inherited eccDNA remained transcriptionally active in progeny, producing transcripts absent from self-grafted controls. Our findings establish eccDNA as heritable extrachromosomal elements that link graft-mediated somatic genetic transfer with stable germline transmission, thereby expanding the molecular scope of heritable variation in plants and providing a conceptual framework for graft-based trait transmission.

plant biology↗

Environmental Regulation and Gene-by-Environment Interaction Influence RAP1 Activity and its Impact on Gene Expression

Gene-by-environment (GxE) interactions play a major role in shaping both phenotypic and molecular variation, with important implications for human health and disease. In this study, we used the Doxycycline (Dox) regulated, tetracycline-responsive (Tet-Off) promoter system to sequentially reduce or titrate gene expression levels of the essential yeast transcription factor Repressor Activator Protein 1 (RAP1) similar to a hypomorph allele series, across three distinct environments: Yeast Peptone Dextrose (YPD) media, YPD media with Heat Shock (HS), and Yeast Peptone Acetate (YPAC) media. We then performed RNA sequencing (RNA Seq) to assess global transcriptional responses to RAP1 reduction in these different growth environments. Our analysis first focused on the independent effects of varying RAP1 expression levels within and across environments. We then explored GxE interactions, revealing a subset of genes with significant consequences of reduced levels of RAP1 and environment-specific expression patterns. Notably, many genes exhibited opposite effects of RAP1 titration on gene expression when yeast were grown in YPAC media compared to YPD media and/or HS, suggesting environment-dependent regulatory architecture. This design reveals how cells integrate internal transcriptional and regulatory changes with external environmental cues, providing a deeper view of GxE architecture. Using Weighted Gene Co-expression Network Analysis (WGCNA), we identified co-regulated gene modules, and by combining this with transcription factor motif enrichment tests, our study identified candidate regulators driving their dynamics. Our findings demonstrate that gene regulatory networks can vary dramatically depending on the environmental context an organism experiences, which can then influence the specific phenotypes produced by a particular genetic perturbation. This illustrates the complexity of genotype-environment interactions and the importance of studying gene function in multiple environments to gain a truly comprehensive understanding of a genes sometimes numerous and diverse functions.

genomics↗

Scalable longitudinal imaging and transcriptomics of cells in dynamic enclosures

Dynamic transitions between cell states underlie both normal physiology and disease. However, most single-cell technologies capture only static snapshots. To address this gap, we developed a platform that integrates light-guided hydrogel polymerization with computer vision to generate on-demand compartments around live cells, enabling longitudinal imaging of cellular behavior paired with whole-transcriptome profiling of the same cells at scale. These data link dynamic phenotypes with molecular programs, enabling deeper characterization of cellular states. This approach revealed an adaptive, drug-resistant state in lung cancer cells characterized by potassium channel upregulation and p53-dependent quiescence. In models of adipogenesis and microglial phagocytosis, joint analysis of imaging and transcriptomic data identified key drivers of cellular function that were missed by transcriptomic clustering alone. These results establish the value of paired functional and transcriptomic analysis to resolve molecular drivers of complex cellular behaviors.

systems biology↗

Linking live-cell behavior to transcriptional responses across perturbations using dynamic caging

Single-cell technologies, encompassing molecular, morphological, and functional assays, have emerged as cornerstones of modern biological research and discovery. However, current experimental methods often fail to explicitly link these omic modalities, especially in live cells or longitudinally through time, impeding the study of multi-scale interactions and mechanisms of regulation. CellCage Enclosure (CCE) technology overcomes these limitations by dynamically compartmentalizing cells, allowing for scalable, live-cell, longitudinal exploration and simultaneous analysis of transcriptomic, proteomic, and morphological profiles. Using this novel technology, we generate previously inaccessible insights across various in vitro cellular systems under a diverse set of perturbations, including the discovery of morphological and proteomic features linked to immune suppressive gene set expression in human primary regulatory T cells (Tregs), as well as direct association of morphological and proteomic features with inflammatory gene modules in human colonic fibroblasts. We then develop a novel pooled CRISPR genetic screening technology using CCEs, PERTURB-LINK (PERTURBational LINKage of transcriptomics and imaging in single cells via enclosure-based screening) and apply this approach in murine bone marrow derived macrophages (BMDMs), enabling multiomic dissection of NF-{kappa}B pathway regulation in response to lipopolysaccharide (LPS) stimulation. Together, these findings demonstrate the broad impact that advancements in live-cell, paired multimodal technologies, especially upon perturbation, may offer in deepening our understanding of cellular biology.

cell biology↗

A Decade of Deep Learning-based Biomedical Image Segmentation

Biomedical image segmentation is a fundamental problem in computational biomedicine that aims to precisely delineate anatomical and biological structures, tissue types, or pathological regions in biomedical images. Accurate segmentation is essential for interpretation, decision-making, and quantitative analysis across a wide range of biological and medical applications. Over the past decade, the field has undergone a profound paradigm shift, evolving from task-specific specialist models to universal foundation models. This review provides an in-depth analysis of the evolution, tracing how the limitations of local discriminative learning drove the transition toward transformer-based global modeling, and large-scale generative pre-training. To help navigate the diverse landscape of interaction paradigms, we introduce the first systematic taxonomy of promptable biomedical image segmentation, categorizing existing methods into six distinct types, enabling users to intuitively select appropriate prompting strategies based on visual demonstrations and quickly pinpoint relevant literature (Prompt Type Visualization). Beyond model architectures, we discuss parallel advancements in dataset development, evaluation protocols, and application-specific adaptations across radiology, pathology, and biology. Integrating these powerful foundation models with rigorous domain-specific adaptation has great potential to improve patient outcomes and healthcare efficiency. Finally, we highlight key challenges in trustworthiness and clinical integration that must be overcome to realize the potential of the next generation of biological and medical generalists.

bioengineering↗

Benchmarking spatial interpolation methods for brain maps

The human brain is a unique biological space that hosts complex processes unfolding at multiple scales. To study these processes, an abundance of imaging technologies evolved over many decades to produce large-scale, dense mappings of structural and functional features. In parallel, a rich universe of techniques for cellular and molecular biology supplies us with fine-scale, highly specific and reliable measurements in sparse tissue samples. To represent cortical processes integratively across scales, spatial interpolation is necessary for bridging dense and sparse data. The absence of a field consensus for realistic interpolation of features over the whole brain prompts a comprehensive comparison of existing frameworks from the broader scientific literature. Here, we benchmark the performance of multiple deterministic (Inverse Distance Weighting, K-Nearest Neighbours, and Radial Basis Function) and stochastic (Spatially-Weighted Regression, Ordinary Kriging, and Regression Kriging) strategies first with simulated or empirical ground truths. We then demonstrate two use cases with de novo sparse brain data (intracranial EEG and microarray gene expression). In these experiments, we investigate how differences in data characteristics, such as spatial dependency structure and sampling distribution, impact the performance of different interpolation methods. Throughout the results, we consistently find that maps interpolated through spatially-informed stochastic frameworks such as Ordinary Kriging and Regression Kriging are more accurate and biologically realistic across geometric constraints, data modalities, and sampling conditions. This invites continued development of spatially-informed statistical frameworks for analyzing brain data and, more fundamentally, the biological processes that produce them.

neuroscience↗

Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8+CD 103+ tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/721223v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@34b2f4org.highwire.dtl.DTLVardef@1d0bb89org.highwire.dtl.DTLVardef@c8277borg.highwire.dtl.DTLVardef@9825ac_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic Abstract:C_FLOATNO Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis C_FIG

immunology↗

YIPPEE/YPEL5 regulates circadian period by modulating PER ubiquitination and stability

Circadian clocks rely on evolutionarily conserved transcriptional-translational feedback loops to align physiology and behavior with the 24-hour day-night cycle. Post-translational modifications, especially ubiquitination, critically control core clock protein stability and circadian pace. In both fruit flies and mammals, the abundance of key pacemaker protein PERIOD (PER/PER2) must be tightly regulated to sustain circadian rhythms. However, the canonical phosphorylation-dependent pathway cannot fully account for turnover of PER in Drosophila. Here we identify Yippee as a critical regulator of PER level through a genetic screen of downregulating ubiquitination pathways. Knockdown of Yippee in circadian pacemaker neurons significantly lengthens the circadian period by [~]2 hours and elevates PER levels. Indeed, YIPPEE physically interacts with PER in fly head. Mechanistically, its mammalian homolog YPEL5 binds PER2, promotes K63-linked polyubiquitination and proteasomal degradation of PER2 independently of FASP-region phosphorylation. Lastly, downregulating YPEL5/Ypel5 prolongs circadian periods in human U2OS cells and mice. Our findings reveal an evolutionarily conserved mechanism in which Yippee/YPEL5 regulates circadian rhythms by mediating ubiquitin-dependent degradation of PER/PER2.

molecular biology↗

Revisiting the Monascus genus (Eurotiales, Aspergillaceae): A Multilocus Phylogenetic Approach to Species Delimitation

Monascus spp. are economically important filamentous fungi that have been utilized in the production of beneficial metabolites such as Monascus pigments and monacolin K, as well as in the brewing of some Asian fermented foods. The delimitation of Monascus species has traditionally relied on phenotypic traits; however, this morphological classification approach is susceptible to subjective judgments and variations in cultural conditions and also may not necessarily be related to the actual genetic relationship. Consequently, synonymy and misidentification frequently occur in Monascus taxonomy, highlighting the urgent need for a convenient and reliable classification system for this genus. In this study, a phylogenetic analysis of 82 representative Monascus strains, encompassing all previously recognized species of the genus, was conducted based on the concordance of five gene genealogies (BenA, CaM, ITS, LSU, and RPB2) to clarify species delimitation and resolve phylogenetic relationships within Monascus. The results revealed that the genus Monascus is resolved into 11 species, which are clustered into two sections: Floridani (including M. argentinensis, M. flavipigmentosus, M. floridanus, M. lunisporas, M. mellicola, M. pallens, and M. recifensis) and Rubri (including M. pilosus, M. purpureus, M. ruber, and M. sanguineus). M. pilosus and M. sanguineus were reaffirmed as distinct species due to their well-supported and divergent phylogenetic lineages. Additionally, M. albidulus, M. anka, M. barkeri, and M. fumeus are synonymized with M. pilosus, while M. aurantiacus and M. rutilus are synonyms of M. purpureus. Finally, a comprehensive list of accepted Monascus species along with their corresponding barcode sequence data is provided.

microbiology↗

Inducible nitric oxide synthase (iNOS) regulates skin eschar lesions, bacterial persistence, and inflammatory resolution in mouse models of scrub typhus

Orientia tsutsugamushi (Ot) is an obligately intracellular bacterium that causes scrub typhus, a potentially severe infectious disease characterized by systemic inflammation and multiorgan dysfunction. We recently reported a protective role for IFN-{gamma} signaling in host defense against Ot infection; however, the underlying mechanisms remain obscure. Inducible nitric oxide synthase (iNOS, encoded by Nos2) is a key antimicrobial effector induced downstream of IFN-{gamma} signaling. Here, we used transgenic mouse models to further investigate the biological functions of iNOS. We first revealed the requirement of iNOS for the restriction of Ot growth in cultured bone marrow-derived macrophages. Using an intradermal mouse model, we found that while tissues of Nos2-/- and wild-type mice exhibited comparable bacterial burdens during acute infection phases, Nos2-/- mice developed eschar-like lesions similar to those observed in Ifngr1-/- mice, indicating a critical role for the IFN-{gamma}/iNOS axis in regulating skin pathology in scrub typhus. Notably, Nos2-/- mice displayed impaired bacterial clearance during the recovery phase (day 42), with persistent bacterial burdens in multiple organs accompanied by sustained immune activation and elevated inflammatory responses. Histopathological and biochemical analyses further revealed increased tissue damage and dysregulated physiological homeostasis in Nos2-/- mice during recovery. Mechanistically, iNOS deficiency resulted in heightened myeloid cell activation and prolonged expression of proinflammatory mediators, suggesting a dual contribution of iNOS in both antimicrobial defense and inflammation resolution. Collectively, these findings provide new insight into IFN-{gamma}-mediated defense mechanisms and imply the distinct roles of iNOS during different stages of scrub typhus. Author summaryScrub typhus is a potentially severe infectious disease caused by the bacterium Orientia tsutsugamushi (Ot), which is transmitted to humans through the bite of infected mites. Despite its global impact and expanding geographic distribution, the immune mechanisms that protect against this infection remain incompletely understood. In this study, we examined the role of inducible nitric oxide synthase (iNOS), an immune effector molecule that helps the host control infection. Using mouse models, we found that iNOS plays dual and stage-specific roles during Ot infection. Mice lacking iNOS developed dysregulated immune homeostasis during acute infection and exhibited skin lesions resembling the eschars observed in some patients with scrub typhus. In addition, these mice showed delayed bacterial clearance, prolonged inflammation, and increased tissue damage during the recovery phase. Our findings indicate that iNOS contributes not only to host antimicrobial defense but also to the control of excessive inflammation following infection. These results provide new insight into host defense mechanisms in scrub typhus and may help inform future therapeutic or preventive strategies.

immunology↗

FOXA1 preserves cell polarity and restrains lysosome biogenesis in non-small cell lung adenocarcinoma

BackgroundThis study investigates the role of the pioneer transcription factor FOXA1 as a master gene in sustaining epithelial cell polarization in early-stage lung adenocarcinoma. The partial loss of FOXA1 is explored to determine if it will affect plasticity and progression of lung adenocarcinoma. The study also addresses the transcriptional circuitry that links polarity defects to lysosome homeostasis. MethodsA multiomics approach was used to define the status of the chromatin in epithelial and mesenchymal states of A549 adenocarcinoma cells obtained with a newly synthetized TGF-{beta} receptor inhibitor or TGF-{beta} respectively. The study leveraged ATAC-seq, RNA sequencing, Cut&Tag sequencing of FOXA1 and histone marks profiling. The functional impact of FOXA1 was examined by partial silencing in vitro and by heterozygous FOXA1 deletion in a KrasG12D mouse model. Three-dimensional organoid culture, high-resolution electron microscopy, spatial transcriptomics and multiplex immunohistochemistry assessed carcinoma cell polarity, proliferation, the tumor microenvironment and organelle content. Group differences were evaluated with two-tailed t tests or one-way analysis of variance. ResultsFOXA1 binding and expression were highest in cells harboring an epithelial phenotype. In mouse KrasG12D LUAD tumors FOXA1 marked polarized, CDH1-positive cells; heterozygous loss diminished CDH1, disrupted apical-basal architecture, lowered organoid-forming efficiency and remodeled the immune microenvironment. Spatial transcriptomics and ultrastructural analyses showed that FOXA1-deficient carcinoma cells accumulated lysosomes, down-regulated vesicle fusion genes of the SNARE family and activated the lysosomal CLEAR gene network. FOXA1 occupied enhancers of lysosome-associated genes and competed with the transcription factor TFE3, thereby suppressing transcription of cathepsin B and cathepsin C and restricting lysosome biogenesis. ConclusionsFOXA1 is a central regulator that preserves epithelial cell polarity and limits lysosome formation in lung adenocarcinoma. Targeting the FOXA1-TFE3-lysosome axis may affect tumor plasticity and provide new therapeutic opportunities.

cancer biology↗

Interplay of the ribosome A and CAR sites

Protein translation is a highly regulated process influenced by multiple factors at the initiation, elongation, and termination stages. One notable regulatory element of the ribosome is the CAR interaction surface, a three-residue motif in the structure of the ribosome composed of C1274 and A1427 of S. cerevisiae 18S rRNA (corresponding to C1054 and A1196 in E. coli 16S rRNA) and R146 of ribosomal protein Rps3. CAR is highly conserved and positioned adjacent to the amino-acyl (A site) decoding center. It establishes hydrogen bonds with the +1 codon next in line to enter the ribosome A site, acting as an extension of the tRNA anticodon and forming base-stacking interactions with nucleotide 34 of the tRNA. However, despite CARs enzymatically strategic positioning within the ribosome, its functional relationship with the A site remains poorly characterized. Using molecular dynamics (MD) simulations, we examined the interplay between the A site and CAR site, revealing sequence-dependent modulation of H-bonding and {pi}-stacking interactions within and between the two sites. These findings highlight the interplay between the A site and CAR site, suggesting a structural and functional connection between these two regions of the ribosome that may contribute to mRNA sequence-specific tuning of translation elongation. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/714784v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1919efaorg.highwire.dtl.DTLVardef@15c4882org.highwire.dtl.DTLVardef@19c7782org.highwire.dtl.DTLVardef@16a1246_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

PA-SfM: Tracker-free differentiable acoustic radiation for freehand 3D photoacoustic imaging

Three-dimensional photoacoustic imaging (3D PAI) has shown great potential in preclinical studies and clinical implementations, while it commonly has sparse sensor arrays, limiting both spatial sampling and the field of view (FOV). Freehand scanning could overcome these limitations through anatomy-adaptive scanning that extends spatial coverage and provides complementary views beyond the fixed array aperture, but its flexibility is conventionally constrained by the need for motor feedback or external pose tracking. Here we introduce PA-SfM, a tracker-free structure-from-motion (SfM) framework that recovers multiple poses directly from PA measurements with superior precision, enabling freehand 3D PAI without external pose measurements. PA-SfM integrates a differentiable acoustic radiation model with hierarchical optimization and rigid array constraints, it jointly estimates inter-view transformations and reconstructs 3D volumes. The performance of PA-SfM was demonstrated in numerical simulations, animal studies and human imaging experiments. Compared with motor encoder-based fusion of the mechanically scanned system, PA-SfM produced sharper and more continuous vascular reconstructions with an expanded FOV. In controlled quantitative validations, PA-SfM achieved high reconstruction fidelity, with PSNR values over 40 dB and SSIM values above 0.98 relative to ground truth or known pose reference reconstructions. These results demonstrate that PA-SfM enables robust freehand 3D PAI, with particular potential for clinical implementation of large-scale freehand imaging. The source code is publicly available at https://github.com/JaegerCQ/PA-SfM.

bioengineering↗

The COX2-PGE2-PKA Axis Suppresses Antiviral Immunity by Inhibiting mtDNA-Dependent STING Activation.

The innate immune cGAS-STING pathway is activated by cytosolic double-stranded DNA (dsDNA) to induce type I interferon (IFN) response, which is essential for mounting the antiviral response. However, STING activation during viral infection is often insufficient to achieve complete viral clearance, suggesting the existence of additional mechanisms that evade its activity. Here, we identified COX2/PGE2 as a negative regulator of STING activation, particularly in response to arising cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, PGE2, through the EP4-cAMP-PKA axis, induces mitophagy to remove defective mitochondria and hence prevent the accumulation of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated type I IFN and antiviral response. Furthermore, we identified STOML2 as a downstream target of PKA that connects mitochondrial quality control with the regulation of innate immune signaling. Together, our findings establish the COX2/PGE2/PKA axis as a negative regulator of mtDNA-STING signaling that may be targeted to potentiate STING-mediated type I IFN and innate immunity. O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/716411v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1c39d56org.highwire.dtl.DTLVardef@18e7c0eorg.highwire.dtl.DTLVardef@172b353org.highwire.dtl.DTLVardef@15b215a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

cell biology↗

DHHC7 palmitoylates KRAS4A and promotes mutant KRAS-driven pancreatic cancers

KRAS mutations underlie many human cancers. While inhibitors such as Sotorasib and Adagrasib targeting KRAS mutants have shown promise, additional strategies are required to address the broader spectrum of KRAS-driven cancers, particularly those displaying drug resistance. Thus, there is a need to better understand KRAS signaling and develop new therapeutic strategies. Here we show that KRAS4A is palmitoylated on Cys180 by a palmitoyl transferase, DHHC7 (gene name ZDHHC7). Palmitoylation promotes KRAS4A plasma membrane localization, and more importantly, nanoclustering. This in turn promotes the activation of ARAF and RAF1, but not BRAF. DHHC7 and KRAS4A Cys180 palmitoylation are important for the normal and anchorage independent growth of pancreatic cancer cell lines. Depletion of ZDHHC7 dramatically inhibits pancreatic tumor growth in mouse xenograft models. These studies provide new understandings about how palmitoylation regulates KRAS4A activity and suggest DHHC7 as a promising new target for KRAS mutant cancers.

cancer biology↗

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗