Biology subjects

Zhao, X.

Publications and source records attributed to Zhao, X..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Single-nucleus RNA sequencing revealed the impact of post-mortem interval on the cellular component and gene expression analysis of mouse brains

Accurate analysis of cell atlas and gene expression in biological tissues using single-nucleus RNA sequencing (snRNA-seq) is dependent on the quality of source material, and post-mortem interval (PMI) is one of the major sources of variation in RNA quality. Although the use of RNA-degraded tissues in transcriptome analysis remains controversial, such samples are sometimes the sole means to address specific questions. Current studies on the impact of PMI on transcriptome data are limited to large-scale RNA-seq, which ignores cellular heterogeneity. Thus, deciphering the non-cell- autonomous effects caused by PMI is imperative for understanding the cellular and molecular disruption it elicits. Here, we investigated the impact of PMI on cellular components and gene expression using snRNA-seq data from mouse brain tissues of post-mortem. We collected samples that were allowed to decay for varying amounts of time at 25{degrees}C prior to snRNA-seq, covering the entire range of RIN values. The different effects on the PMI to the degradation rate of mRNA and rRNA within nuclei, and the mRNA presented a more stable state. Multi-channel analysis revealed the preferential transient depletion oligodendrocytes and OPCs with increasing PMI. In addition, a rapid widespread overregulation of ribosomal transient recruitment to protein (RP) genes in various cells, and reached a plateau at PMI of 36h. Although state depletion of neuronal cells was not detected, we reported significant upregulation of PMI-dependent RP genes in its subpopulations and their cell loss. Moreover, RP genes showed the greatest differential expression in the subpopulations with greater cell perturbation, and we speculated that aberrant expression of these genes might be associated with cell death. In this study, we systematically investigated the changes in the transcriptome profile of brain tissue induced by PMI at single-cell resolution, and revealed one of the important factors that might be responsible for the changes. In addition, our data complemented a possible explanation for the changes in the cellular state of brain tissue induced by postmortem hypoxia-ischemia, and provided a reference for transcriptome studies of RNA degradation samples.

molecular biology↗

bioRxiv2025

Theory of non-dilute binding and surface phase separation applied to membrane-binding proteins

Surface binding and surface phase separation of cytosolic scaffold proteins on lipid membranes are involved in many cellular processes, such as cell signaling, cell adhesion, and cortex regulation. However, the interplay between surface binding and surface phase separation is poorly understood. In this work, we study this interplay by deriving a general thermodynamic model and applying it to in vitro reconstitution experiments of membrane-binding proteins involved in tight junction initiation. Our theory extends the classical surface binding isotherm to account for non-dilute and heterogeneous conditions where components can phase separate. We use our theory to demonstrate how surface phase separation is governed by the interaction strength among membrane-bound scaffold proteins and their binding affinity to the membrane surface. Comparing the theory to reconstitution experiments, we show that tuning the oligomerization state of the adhesion receptors in the membrane controls surface phase transition and patterning of the scaffold protein ZO1. These findings suggest a fundamental role of the interplay between non-dilute surface binding and surface phase separation in forming the tight junction. More broadly, our work highlights non-dilute surface binding and surface phase separation as a common organizational principle for membrane-associated structures in living cells.

biophysics↗

bioRxiv2024

LINC00599 Promotes Pulmonary Hypertension via LLPS with G3BP1 and MYH9

BACKGROUNDPulmonary hypertension (PH) represents a significant cardiovascular disorder marked by both functional and structural alterations within the pulmonary vasculature. Long non-coding RNAs (lncRNAs) have been closely associated with the pathogenesis and progression of PH. Nonetheless, the precise mechanisms by which lncRNAs interact with its downstream target molecules to modulate the disease remain inadequately elucidated. METHODSThe expression levels of LINC00599 were quantified in the lung tissues of mice and pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions. The involvement of LINC00599 in the progression of PH and vascular remodeling was evaluated through in vivo studies. To investigate the mechanisms by which LINC00599 influences the proliferation of human PASMCs, small interfering RNA and overexpression plasmids were employed. RESUITSThe expression of LINC00599 is upregulated in the medial layer of pulmonary arteries in experimental models of PH and in hypoxic PASMCs. Administration of a single dose of lentivirus-mediated shRNA targeting LINC00599 effectively reverses hypoxic PH in murine models. LINC00599 plays a critical role in PASMC proliferation by modulating stress granule formation through N6-methyladenosine (m6A) modification and promoting proliferation via liquid-liquid phase separation with myosin heavy chain 9. Furthermore, the expression of LINC00599 is regulated by a super-enhancer, which is mediated by the transcription factor ZNF263. CONCLUSIONSThese findings demonstrate for the first time that LINC00599, involved in liquid-liquid phase separation, facilitates the progression of pulmonary hypertension by enhancing the proliferation of pulmonary artery smooth muscle cells. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/629439v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@7ac192org.highwire.dtl.DTLVardef@13a88b3org.highwire.dtl.DTLVardef@1e4c761org.highwire.dtl.DTLVardef@ddd105_HPS_FORMAT_FIGEXP M_FIG C_FIG What Is New?This study identified LINC00599 as a critical regulator of liquid-liquid phase separation through m6A modification and as a pivotal target in promoting the progression of PH. What Is Relevant?LncRNAs are intricately associated with the pathogenesis and progression of PH through the modulation of downstream target molecules. However, it remains unclear whether lncRNAs contribute to PH by forming specific subcellular structures with these target molecules. Furthermore, some studies have suggested that the increased presence of stress granules in PASMCs is implicated in the pathogenesis of pulmonary arterial hypertension. In this study, we provide evidence that LINC00599 promotes the development of PH by forming stress granules with its target proteins. Our findings indicate that the binding of LINC00599, modified with m6A, to G3BP1 and MYH9 in PASMCs suggests that the regulation of liquid-liquid phase separation by lncRNA m6A modification may represent a significant pathological mechanism underlying PH. What Are the Pathophysiological Implications?We found that LINC00599 levels were elevated in hypoxic PASMCs and experimental PH models. Knockout LINC00599 effectively prevented PH, indicating its potential as both a bomarker and therapeutic target for PH.

physiology↗

bioRxiv2024

Deciphering single-cell heterogeneity and cellular ecosystem dynamics during prostate cancer progression

Prostate cancer (PC) progresses from benign epithelium through pre-malignant lesions, localized tumors, metastatic dissemination, and castration-resistant stages, with some cases exhibiting phenotype plasticity under therapeutic pressure. However, high-resolution insights into how cell phenotypes evolve across successive stages of PC remain limited. Here, we present the Prostate Cancer Cell Atlas (PCCAT) by integrating [~]710,000 single cells from 197 human samples covering a spectrum of tumor stages. This comprehensive analysis dissects the cellular landscape and characterizes key cell types and molecular features that associate with PC progression and prognosis. In malignant cells, we highlight a distinctive profile denoted by high Major Histocompatibility Complex (MHC) expression, low Androgen Receptor (AR) activity, and enhanced stemness programs associated with enzalutamide resistance. Moreover, we reveal several cell states strongly correlated with PC progression and adverse prognosis, including lineage plasticity-like malignant cells (LPCs), neuroendocrine tumor cells, pericytes, and matrix cancer-associated fibroblasts (mCAFs). Furthermore, we uncover shared cell states that underpin the immune suppressive tumor microenvironment in advanced PC, including activated regulatory T cells, exhausted CD8+ T cells, and SPP1-expressing macrophages. Lastly, we pinpoint a spatial niche composed of mCAFs and SPP1-expressing macrophages localized near the tumor boundary in aggressive PC, which correlates with poor prognosis. Overall, our work provides a valuable resource and offers deeper insights into the diverse cell states, dynamics, and functional characteristics involved in PC progression at single-cell resolution.

cancer biology↗

bioRxiv2024

Silicon-rhodamine-enabled Identification (SeeID) for Near-Infrared Light Controlled Proximity Labeling In Vitro and In Vivo

Advancement in fluorescence imaging techniques enables the study of protein dynamics and localization with unprecedented spatiotemporal resolution. However, current imaging tools are unable to elucidate dynamic protein interactomes underlying imaging observations. In contrast, proteomics tools such as proximity labeling enable the analysis of protein interactomes at a single time point but lack information about protein dynamics. We herein developed Silicon-rhodamine-enabled Identification (SeeID) for near-infrared light controlled proximity labeling that could bridge the gap between imaging and proximity labeling. SeeID was benchmarked through characterization of various organelle-specific proteomes and the KRAS protein interactome. The fluorogenic nature of SiR allows for intracellular proximity labeling with high subcellular specificity. Leveraging SiR as both a fluorophore and a photocatalyst, we developed a protocol that allows the study of dynamic protein interactomes of Parkin during mitophagy. We discovered the association of the proteasome complex with Parkin at early time points, indicating the involvement of the ubiquitin-proteasome system for protein degradation in the early phase of mitophagy. In addition, by virtue of the deep tissue penetration of near-infrared light, we achieved spatiotemporally controlled proximity labeling in vivo across the mouse brain cortex with a labeling depth of [~]2 mm using an off-the-shelf 660 nm LED light set-up.

molecular biology↗

bioRxiv2024

PRMT1-Mediated Metabolic Reprogramming Promotes Leukemogenesis

Copious expression of protein arginine methyltransferase 1 (PRMT1) is associated with poor survival in many types of cancers, including acute myeloid leukemia. We observed that a specific acute megakaryocytic leukemia (AMKL) cell line (6133) derived from RBM15-MKL1 knock-in mice exhibited heterogeneity in Prmt1 expression levels. Interestingly, only a subpopulation of 6133 cells expressing high levels of Prmt1 caused leukemia when transplanted into congenic mice. The PRMT1 inhibitor, MS023, effectively cured this PRMT1-driven leukemia. Seahorse analysis revealed that PRMT1 increased the extracellular acidification rate (ECAR) and decreased the oxygen consumption rate (OCR). Consistently, PRMT1 accelerated glucose consumption and led to the accumulation of lactic acid in the leukemia cells. The metabolomic analysis supported that PRMT1 stimulated the intracellular accumulation of lipids, which was further validated by FACS analysis with BODIPY 493/503. In line with fatty acid accumulation, PRMT1 downregulated the protein level of CPT1A, which is involved in the rate-limiting step of fatty acid oxidation. Furthermore, administering the glucose analogue 2-deoxy-glucose (2-DG) delayed AMKL progression and promoted cell differentiation. Ectopic expression of Cpt1a rescued the proliferation of 6133 cells ectopically expressing PRMT1 in the glucose-minus medium. In conclusion, PRMT1 upregulates glycolysis and downregulates fatty acid oxidation to enhance the proliferation capability of AMKL cells. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/628174v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1ae96borg.highwire.dtl.DTLVardef@d27916org.highwire.dtl.DTLVardef@ba63corg.highwire.dtl.DTLVardef@cee9af_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Temporal Configuration as a New Feature of Sound: Psychological and Neurophysiological Evidence, Cross-species Consistency and Underlying Neuronal Mechanisms

Natural sounds are defined not only by their spectral content but also by their fine temporal structure. Here we show that millisecond-scale temporal configuration--defined by the ordering of inter-click intervals (ICIs) within a click train--behaves as a distinct auditory feature, conserved across species and emerging hierarchically along the auditory pathway. Human listeners reliably discriminated click trains that shared the same average ICI but differed in temporal configuration, and these differences elicited robust mismatch negativity (MMN) responses in an oddball paradigm, indicating automatic cortical deviance detection. Awake rats showed analogous MMN-like ECoG responses to configuration changes, demonstrating cross-species generality. Neuropixels recordings along the inferior colliculus-medial geniculate body-primary auditory cortex (IC-MGB-A1) axis revealed minimal configuration sensitivity in IC, intermediate sensitivity in MGB, and strong stimulus-specific adaptation to temporal configuration in A1. Reversible cooling of auditory cortex reduced configuration sensitivity in MGB, implicating corticothalamic feedback in shaping thalamic representations. Layer-resolved analyses further showed that supragranular A1 neurons carry stronger configuration-specific adaptation than infragranular neurons. These findings identify temporal configuration as a feature-like dimension of sound and delineate a hierarchical, feedback-dependent IC-MGB-A1 circuit architecture for encoding fine temporal structure in the mammalian brain.

neuroscience↗

bioRxiv2024

Quantitative Spatial Analysis of Chromatin Biomolecular Condensates using Cryo-Electron Tomography

Phase separation is an important mechanism to generate certain biomolecular condensates and organize the cell interior. Condensate formation and function remain incompletely understood due to difficulties in visualizing the condensate interior at high resolution. Here we analyzed the structure of biochemically reconstituted chromatin condensates through cryo-electron tomography. We found that traditional blotting methods of sample preparation were inadequate, and high-pressure freezing plus focused ion beam milling was essential to maintain condensate integrity. To identify densely packed molecules within the condensate, we integrated deep learning-based segmentation with novel context-aware template matching. Our approaches were developed on chromatin condensates, and were also effective on condensed regions of in situ native chromatin. Using these methods, we determined the average structure of nucleosomes to 6.1 and 12 [A] resolution in reconstituted and native systems, respectively, and found that nucleosomes form heterogeneous interaction networks in both cases. Our methods should be applicable to diverse biochemically reconstituted biomolecular condensates and to some condensates in cells.

biophysics↗

bioRxiv2024

A signal of temporal integration in the human auditory brain: psychological insights, EEG evidence, and clinical application

Temporal integration, the process by which the auditory system combines sound information over a curtain period to form a coherent auditory object, is essential for coherent auditory perception, yet its neural mechanisms remain underexplored. We use a "transitional click train" paradigm, which concatenates two click trains with slightly differing inter-click intervals (ICIs), to investigate temporal integration in the human cortex. Using a 64-channel electroencephalogram (EEG), we recorded responses from 42 healthy participants exposed to regular and irregular transitional click trains and conducted change detection tasks. Regular transitional click trains elicited significant change responses in the human cortex, indicative of temporal integration, whereas irregular trains did not. These neural responses were modulated by ICI length, ICI contrast, and regularity. Behavioral data mirrored EEG findings, showing enhanced detection for regular conditions compared to irregular conditions and pure tones. Furthermore, variations in change responses were associated with decision-making processes. Temporal continuity was critical, as introducing gaps between click trains diminished both behavioral and neural responses. In clinical assessments, 22 coma patients exhibited diminished or absent change responses, effectively distinguishing them from healthy individuals. Our findings identify distinct neural markers of temporal integration and highlight the potential of transitional click trains for clinical diagnostics.

neuroscience↗

bioRxiv2024

The evolution of irreversible cell differentiation under cell death effect

Cell differentiation is an important characteristic of multicellular organisms which produce new-typed cells to engage in diverse life functions. Irreversible differentiation, as an important differentiation, describes cells differentiated by determined trajectories to form specialized cell types. It has been found that differentiated cell types often show different death rates. Yet, it is still unclear what role cell death plays in shaping the formation of irreversible cell differentiation. Here, we establish a theoretical model to investigate the impact of cell death on the evolution of irreversible cell differentiation in multicellular organisms. Irreversible differentiation refers to the loss of a cell types differentiation potential, and it is constructed by the sequences of differentiation probabilities of a cell type across cell divisions. We show that irreversible differentiation is more likely to occur when cell death rates between cell types are linear. Meanwhile, differences in death rates between cell types affect the emergence conditions of irreversible differentiation, whereas no significant impacts on that from equal cell death rates. Additionally, we found that cell death impacts the cell number and cell composition of a mature organism. These findings provide insights into understanding the role of cell death in the formation of cells irreversible differentiation.

evolutionary biology↗

bioRxiv2024

Advanced Bioprinting of Hydrogels with Controlled Mineral Gradients for Regenerative Engineering of the Osteochondral Interface

The osteochondral (OC) interface exhibits a mineral gradient in the subchondral bone and articular cartilage interface, varying in thickness by several hundred micrometers across different species. Disruptions to this interface can cause severe damage to OC tissues, leading to osteoarthritis (OA), a debilitating and irreversible condition. Regenerative engineering approaches hold promise for addressing this issue by replicating the natural architecture and composition of native OC interface within a biomaterial scaffold. This study introduces a novel one-step bioprinting process using a twin-screw extruder that facilitates the fabrication of a unitary synthetic graft (USG), which mimics the native OC interfaces mineral concentration gradient. The newly developed USG is composed of an agarose-based cartilage layer and a bone layer, which consists of agarose enriched with 20% hydroxyapatite (w/vol). The USG features a gradient interface with the mineral concentration seamlessly transitioning from 0 to 20wt% from the cartilage to the bone layer. The mineral gradients in the USG and the native tissue were documented using thermogravimetric analysis (TGA), micro-CT, and energy dispersive x-ray (EDX). TGA revealed that the gradient transition length in the graft (647{+/-}21m) compared well to that of native OC tissue (633{+/-}124m) harvested from bovine knee. The strain sweep and frequency sweep tests in oscillatory shear evaluated the linear viscoelastic properties of the grafts, indicating a dominant storage modulus over loss modulus similar to that of native OC tissues. Additionally, the compressive and stress relaxation behaviors of the USGs were quantified using multi-extensional tests, highlighting the grafts ability to maintain structural integrity under mechanical stress. Furthermore, viability assays performed after bioprinting showed that chondrocytes and human fetal osteoblast cells successfully integrated and survived within their designated regions of the graft. The USGs engineered in this study exhibit properties that make them promising candidates for regenerating OC defects and restoring knee joint functionality.

bioengineering↗

bioRxiv2024

Pharmacological inhibition of SUMOylation recapitulates genetic hypoSUMOylation in the murine epididymal white adipose tissue

Post-translational modification by the small ubiquitin-like modifier (SUMO) is essential for cellular differentiation and homeostasis. Here, we investigate the role of SUMOylation in adipose tissue development using TAK-981, a pharmacological inhibitor of SUMOylation. Administration of TAK-981 to mice resulted in significant defect in weight gain and adipocyte atrophy in perigonadal white adipose tissue (gWAT) depots. Gene expression analyses revealed a marked downregulation of adipogenic genes, including Pparg, Cebpa, and Fasn. Our data thus indicate that TAK-981 treatment impaired adipogenesis in gWAT, consistent with prior findings that SUMOylation supports transcriptional regulation of adipogenesis and lipid metabolism. We also found significant infiltration of immune cells and efferocytosis in gWAT. Our results thus indicate that SUMOylation inhibition using a small molecule phenocopies genetic hypoSUMOylation models, highlighting its critical role in maintaining adipocyte functionality and immune environment. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our results underscore the importance of considering the potential unintended effects of SUMOylation inhibition on adipose tissue in patients.

developmental biology↗

bioRxiv2024

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↗

bioRxiv2024

Positive impact of Type-A and -C response regulator genes on growth and panicle architecture in rice

Cytokinin signal transduction occurs through a "two-component system." Type-A and -C response regulators (RRs) are groups of proteins of similar structures constituting significant components of cytokinin signal transduction. In rice, 13 (Type-A) and two (Type-C) RRs have been identified to date; however, their functions remain partially known. In this study, we examined the expression patterns of Type-A and Type-C RRs in rice using RNA-Seq and confirmed their functions by constructing mutants of the 15 genes with CRISPR/Cas9. Almost all Type-A RRs played positive roles in the development of secondary branches and secondary spikelets, particularly RR2 and RR4. Notably, rr1 rr2 and rr8 rr12 rr13 higher-order mutants displayed small panicle sizes and decreased plant height. Additionally, both Type-C RRs played positive roles in regulating heading date. RNA-seq revealed several genes with significantly altered expression in the rr2 and rr4 mutants, with almost half of the differentially expressed genes (DEGs) overlapping between the two mutants. Many of the DEGs were associated with the cytokinin and abscisic acid pathways. Our findings provide new insights into the functions of Type-A and -C RRs in rice growth and may serve as a foundation for future studies focusing on cytokinin signaling.

plant biology↗

bioRxiv2024

A polyketide-based biosynthetic platform for diols, amino alcohols and hydroxyacids

Medium- and branched-chain diols and amino alcohols are important industrial solvents, polymer building blocks, cosmetics and pharmaceutical ingredients, yet biosynthetically challenging to produce. Here, we present a novel approach utilising a modular polyketide synthase (PKS) platform for the efficient production of these compounds. This platform takes advantage of a versatile loading module from the rimocidin PKS and NADPH-dependent terminal thioreductases (TRs), previously untapped in engineered PKSs. Reduction of the terminal aldehyde with specific alcohol dehydrogenases enables production of diols, oxidation enables production of hydroxy acids, and transamination with specific transaminases enables production of various amino alcohols. Furthermore, replacement of the malonyl-coenzyme A (CoA)-specific acyltransferase (AT) in the extension module with methyl- or ethylmalonyl- CoA-specific ATs enables production of branched-chain diols and amino alcohols. In total, we demonstrated production of nine 1,3-diols (including the difficult-to-produce insect repellent and cosmetic ingredient 2-ethyl-1,3-hexanediol), six amino alcohols, and two carboxylic acids using our PKS platform in Streptomyces albus. Finally, tuning production of the PKS acyl-CoA substrates enabled production of high titers of specific diols and amino alcohols (1 g/L diol titer in shake flasks), demonstrating high tunability and efficiency of the platform.

bioengineering↗

bioRxiv2024

Inhibition of H3K27M-enhanced ATM signaling increases radiation efficacy in diffuse midline glioma

H3K27-altered diffuse midline glioma (DMG) is an aggressive and treatment-resistant form of pediatric high-grade glioma (pHGG). The disease is defined by point mutations in histone H3 that convert lysine 27 to methionine (termed H3K27M), resulting in genome-wide epigenetic changes that drive tumorigenesis. While radiation therapy is the standard of care, subsequent recurrence, often within the high dose radiation field, is universal. We found that the apical DNA damage response (DDR) kinase Ataxia Telangiectasia-Mutated (ATM) was uniquely upregulated in H3K27M-expressing patient tumor samples compared to pHGG expressing only wild-type histone H3. Using a panel of H3K27 isogenic DMG cell lines, we further found that H3K27M was associated with reduced H3K27me3 within the ATM promoter, increased ATM mRNA levels, and elevated DDR signaling, even in the absence of exogenous DNA damage. Consistent with these results, AZD1390, a clinical-grade, CNS-penetrant ATM inhibitor, sensitized H3K27M neurospheres to the long-term effects of radiation on survival, in part due to attenuated repair of radiation-induced DNA damage. Finally, AZD1390 sensitized orthotopic H3K27M mutant tumors to radiotherapy and significantly extended median survival relative to vehicle, AZD1390 or radiation alone (50 days vs 31, 36 or 39 days, respectively) with minimal adverse effects. Taken together, these data provide a direct mechanistic link between the H3K27M mutation and ATM expression and support the clinical investigation of AZD1390 with radiotherapy in H3K27M-altered DMG.

cancer biology↗

bioRxiv2024

Connectomic Organization of the Suprachiasmatic Nucleus

The suprachiasmatic nucleus (SCN), the mammalian master clock, is a special structure dedicated to the time computation. However, a connectomic understanding of the nucleus as a whole is lacking. Using serial section electron microscopy, we reconstructed multiscale and multimodal SCN communication networks. Intra-SCN synaptic network consists of 9,566 morphologically similar neurons and 4.3 million synapses, organized into multiscale circuitries that interact with SCN-traversing axon fascicles. Strikingly, SCN neurons engage in unique soma-soma ephaptic interaction, forming 2,038 electrotonic integrative units with the largest overlapping the light-responsive area (LRA). SCNs paracrine modality contains 47,396 m3 dense core vesicles, with notable scarcity in the LRA, suggesting cross-modal coordination and functional integration. These distinct network features provide comprehensive insights into the system architecture of the mammalian circadian clock.

neuroscience↗

bioRxiv2024

Expression-Driven Genetic Dependency Reveals Targets for Precision Medicine

Cancer cells are heterogeneous, each harboring distinct molecular aberrations and are dependent on different genes for their survival and proliferation. While successful targeted therapies have been developed based on driver DNA mutations, many patient tumors lack druggable mutations and have limited treatment options. Here, we hypothesize that new precision oncology targets may be identified through "expression-driven dependency", whereby cancer cells with high expression of a targeted gene are more vulnerable to the knockout of that gene. We introduce a Bayesian approach, BEACON, to identify such targets by jointly analyzing global transcriptomic and proteomic profiles with genetic dependency data of cancer cell lines across 17 tissue lineages. BEACON identifies known druggable genes, e.g., BCL2, ERBB2, EGFR, ESR1, MYC, while revealing new targets confirmed by both mRNA- and protein-expression driven dependency. Notably, the identified genes show an overall 3.8-fold enrichment for approved drug targets and enrich for druggable oncology targets by 7 to 10-fold. We experimentally validate that the depletion of GRHL2, TP63, and PAX5 effectively reduce tumor cell growth and survival in their dependent cells. Overall, we present the catalog of express-driven dependency targets as a resource for identifying novel therapeutic targets in precision oncology.

genomics↗