Biology subjects

Zhang, B.

Publications and source records attributed to Zhang, B..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

The mitochondrial stress- induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing) promotes glioblastoma tumorigenesis by modulating mitochondrial functions

The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in glioblastoma (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential ({Delta}{Psi}m) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth. Impact StatementThe Carboxyl-Terminal Alanine-Threonine-tailed protein ATP5 helps glioblastoma mitochondria maintain a high membrane potential and keep the permeability transition pore closed, thereby promoting tumor growth and increasing resistance to apoptosis. HighlightsO_LIGlioblastoma (GBM) cells have a disturbed RQC pathway C_LIO_LImsiCAT-tailing on ATP5 in GBM cells increases mitochondrial membrane potential C_LIO_LIThis msiCAT-tailing prevents MPTP opening C_LIO_LIATP5 msiCAT-tailing also inhibits drug-induced apoptosis in GBM cells C_LIO_LIBlocking msiCAT-tailing impedes the overall growth of GBM cells C_LI

cancer biology↗

bioRxiv2024

Single-cell transcriptomics reveals immunosuppressive microenvironment and highlights stumor-promoting macrophage cells in Glioblastoma

Glioblastoma (GBM) is the most prevalent and aggressive primary brain malignancy in adults. Nevertheless, the cellular heterogeneity and complexity within the GBM microenvironment (TME) are still not fully understood, posing a significant obstacle in the advancement of more efficient immunotherapies for GBM. In this study, we conducted an integrated analysis of 48 tumor fragments from 24 GBM patients at the single-cell level, uncovering substantial molecular diversity within immune infiltrates. We characterized molecular signatures for five distinct tumor-associated macrophage (TAM) subtypes. Notably, the TAM_MRC1 subtype displayed a pronounced M2 polarization signature. Additionally, we identified a subtype of natural killer (NK) cells, designated CD56dim_DNAJB1. This subtype is characterized by an exhausted phenotype, evidenced by an elevated stress signature and enrichment in the PD-L1/PD-1 checkpoint pathway. Our findings also highlight significant cell-cell interactions among malignant glioma cells, TAM, and NK cells within the TME. Overall, this research sheds light on the functional heterogeneity of glioma and immune cells in the TME, providing potential targets for therapeutic intervention in this immunologically cold cancer.

cancer biology↗

bioRxiv2024

Stabilizing mammalian RNA thermometer confers neuroprotection in subarachnoid hemorrhage

Mammals tightly regulate their core body temperature, yet how cells sense and respond to small temperature changes at the molecular level remains incompletely understood. Here, we discover a significant enrichment of RNA G-quadruplex (rG4) motifs around splice sites of cold-repressed exons. These thermosensing RNA structures, when stabilized, mask splice sites, reducing exon inclusion. Focusing on cold-induced neuroprotective RBM3, we demonstrate that rG4s near splice sites of a cold-repressed poison exon are stabilized at low temperatures, leading to exon exclusion. This enables evasion of nonsense-mediated decay, increasing RBM3 expression at cold. Additionally, increasing intracellular potassium concentration stabilizes rG4s and enhances RBM3 expression, leading to RBM3-dependent neuroprotection in a mouse model of subarachnoid hemorrhage. Our findings unveil a mechanism how mammalian RNAs directly sense temperature and potassium perturbations, integrating them into gene expression programs. This opens new avenues for treating diseases arising from splicing defects and disorders benefiting from therapeutic hypothermia. HighlightsO_LIrG4s are enriched near splice sites of cassette exons repressed upon cold shock C_LIO_LIrG4s act as RNA thermometers in mammals by controlling accessibility of splice sites C_LIO_LIrG4 stability mediates temperature-dependent RBM3 expression ex vivo and in vivo C_LIO_LIStabilizing rG4s in RBM3 exon 3a reduces brain damage in subarachnoid hemorrhage C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=137 SRC="FIGDIR/small/594628v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@e1d625org.highwire.dtl.DTLVardef@b22d21org.highwire.dtl.DTLVardef@1b0faeaorg.highwire.dtl.DTLVardef@294ac1_HPS_FORMAT_FIGEXP M_FIG C_FIG Here is a refined model of RNA G-quadruplexes acting as evolutionarily conserved thermo- and potassium sensors, modulating alternative splicing in mammals. RNA G-quadruplexes (rG4s) function as reversible temperature sensors, impacting alternative splicing dynamics. In low temperatures or high potassium conditions, rG4s can mask surrounding splice sites, rendering these sites inaccessible, thereby promoting exon skipping. Conversely, at high temperatures or under low potassium conditions, rG4s become destabilized, allowing splice sites to be exposed, and facilitating efficient exon inclusion. RBM3, a well-known cold-induced protein with neuroprotective functions, harbors a poison exon with rG4s around splice sites, that, upon inclusion, triggers NMD (non-sense mediated decay) of the RBM3 mRNA. Under low temperatures or high potassium conditions, rG4s shield the splice sites, leading to poison exon skipping and increased RBM3 expression. Stabilization of these rG4s through increased K+ promotes poison exon skipping, enabling escape from NMD, and ultimately elevating RBM3 expression. Notably, 4-AP, a clinically used pan voltage-gated potassium channel blocker, protects against neuronal damage in a subarachnoid hemorrhage mouse model in an RBM-dependent manner. (ISS: intronic splicing silencer, ESE: exon splicing enhancer, ACA: anterior cerebral artery, MCA: middle cerebral artery, PPA: pterygopalatine artery, ICA: internal carotid artery, ECA: external carotid artery, CCA: common carotid artery)

molecular biology↗

bioRxiv2024

NEK1 modulates neurite outgrowth in motor neurons through coordinating retromer formation

Loss of function of a cell cycle-associated gene NEK1 causes amyotrophic lateral sclerosis (ALS), but how this leads to motor neuron degeneration is unknown. We studied the function of NEK1 in human stem cell-derived motor neurons and found that loss of NEK1 causes decreased neurite length accompanied by transcriptional alterations. We also found that NEK1 interacts with and modulates the formation of the retromer, and that impaired retromer function contributes to neurite outgrowth deficits. We identified SMC3, which interacts with NEK1 during the cell cycle, as a kinase substrate of NEK1 in motor neurons. Notably, loss of SMC3 not only recapitulates the decreased neurite outgrowth, but also affects retromer formation. We suggest that NEK1 interacts with multiple proteins in postmitotic neurons to coordinate retromer formation, and that loss of this leads to impaired neurite outgrowth.

neuroscience↗

bioRxiv2024

Precise Generation of Conformational Ensembles for Intrinsically Disordered Proteins Using Fine-tuned Diffusion Models

Intrinsically disordered proteins (IDPs) play pivotal roles in various biological functions and are closely linked to many human diseases including cancer, diabetes and Alzheimer disease. Structural investigations of IDPs typically involve a combination of molecular dynamics (MD) simulations and experimental data to correct for intrinsic biases in simulation methods. However, these simulations are hindered by their high computational cost and a scarcity of experimental data, severely limiting their applicability. Despite the recent advancements in structure prediction for structured proteins, understanding the conformational properties of IDPs remains challenging partly due to the poor conservation of disordered protein sequences and limited experimental characterization. Here, we introduce IDPFold, a method capable of generating conformational ensembles for IDPs directly from their sequences using fine-tuned diffusion models. IDPFold bypasses the need for Multiple Sequence Alignments (MSA) or experimental data, achieving accurate predictions of ensemble properties across numerous IDPs. By sampling conformations at the backbone level, IDPFold provides more detailed structural features and more precise property estimation compared to other state-of-the-art methods. IDPFold is ready to be used in the elucidate the sequence-disorder-function paradigm of IDPs.

bioinformatics↗

bioRxiv2024

Targeting oncogenic K-Ras mutants with a small-molecule degrader through Nedd4-1

K-Ras mutations represent a most prevalent oncogenic alteration in human cancers. Despite of tremendous efforts, it remains a big challenge to develop inhibitors that can target the oncogenic K-Ras mutants, especially mutants without specific active or charged side chains such as K-RasG12V. Here, taking advantage of our previous finding that Nedd4-1 is a bona fide E3 ubiquitin ligase for wild-type Ras proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-Ras mutants including K-RasG12V, and significantly inhibit proliferation and tumor development of K-Ras mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of Nedd4-1 and an allosteric site of K-Ras to enhance Nedd4-1 and K-Ras interaction, and to induce a conformational change of Nedd4-1/K-Ras complex to allow Nedd4-1 targeting K128 of K-Ras for ubiquitination. Hence, our study presents a robust strategy to develop small-molecule degrader of K-Ras mutants, and also sheds light on the development of small-molecule degraders for H-Ras and N-Ras mutants.

cancer biology↗

bioRxiv2024

Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

AbstractO_ST_ABSIntroductionC_ST_ABSAlzheimers disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. MethodsDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). ResultsAs a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. DiscussionThis comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

neuroscience↗

bioRxiv2024

Glial state changes and neuroinflammatory RIPK1 signaling are a key feature of ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron loss in the brain and spinal cord. Neuroinflammation driven by activated microglia and astrocytes is prominent in ALS, but an understanding of cell state dynamics and which pathways contribute to the disease remains unclear. Single nucleus RNA sequencing of ALS spinal cords demonstrated striking changes in glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. Activation of the necroptosis pathway in ALS spinal cords was confirmed in a large bulk RNA sequencing dataset and at the protein level. Blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses in SOD1G93A mice. We used a human iPSC-derived motor neuron, astrocyte, and microglia tri-culture system to identify potential biomarkers secreted upon RIPK1 activation, inhibited pharmacologically in vitro, and modulated in the CSF of people with ALS treated with a RIPK1 inhibitor. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

neuroscience↗

bioRxiv2024

Unveiling Ageing-Associated and Caloric Restriction-Associated Changes in miRNA Expression in Rat Skeletal Muscle and the Mechanisms Mediating their Effects on Muscle Cell Function

The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised 45.5% to youthful levels. Our results suggested miRNAs upregulated with age to downregulated proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results found miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity and the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in culture C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide useful information regarding how miRNA expression changes in skeletal muscle, as well as the consequences of these changes and how they are ameliorated by CR.

molecular biology↗

bioRxiv2024

Transcriptional activation of Bmal1 drives the inflammatory activity of monocytes by modulating mitochondrial unfolded protein response during hypobaric hypoxic stress

BackgroundHypoxic stress-induced inflammation had been considered to play an important role in the onset and progression of altitude-related illnesses, but the origin of inflammatory cytokines, the specific responding cell types, and molecular mechanisms remain unknown. Mitochondria are responsible for oxygen consumption and recently reported to be the master regulators of inflammation, but it is not clear whether and how mitochondrial organelles sense the hypoxic stress and then control the inflammation. MethodsHuman subjects and mouse models were exposed to real or simulated altitude of 5500 m. Bone marrow-derived macrophages (BMDMs) and monocyte RAW264.7 cells were cultured under 1% oxygen hypoxic conditions. Myeloid-specific Bmal1 knock-out mice were generated by crossing Bmal1flox/flox mice with Lyz2-Cre mice. Inflammation was investigated by assessing inflammatory mediators, monocyte activities, and leukocyte infiltrating. Mitochondrial unfolded protein response was examined by measuring stress markers, such as LONP1, AFG3L2, and HSP60. The target molecular mechanisms were identified by performing bioinformatic analyses, ChIP assays, and gain/loss-of-function experiments. Results1) Monocytes in peripheral blood mononuclear cell (PBMCs) were more sensitive and contributed promptly to circulating inflammation in response to acute hypobaric hypoxia. 2) Hypoxic stress triggered the mitochondrial unfolded protein response and then induced the mito-inflammation (NLRP3 inflammasome) in monocytes. 3) Activation of Bmal1 drove mitochondrial stress and mito-inflammation by promoting Fis1-mediated mitochondrial fission in monocytes under hypoxia. 4) BHLHE40, a stress-responsive transcription factor directly targeted by HIF-1, stimulated Bmal1 transcription in monocytes under hypobaric hypoxia. 5) Myeloid-specific Bmal1 deletion alleviated systemic circulating and vascular inflammation under acute hypobaric hypoxia. ConclusionBHLHE40, a transcription factor associated with hypoxia, stimulated Bmal1, which in turn triggered the mitochondrial unfolded protein response and drove the mito-inflammation in monocytes by promoting Fis1-mediated mitochondrial fission. Our work provides a novel mechanism which may develop the circadian targeting drugs for altitude or hypoxia-related diseases.

molecular biology↗

bioRxiv2024

Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas CD4_CTL precursors were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift-myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model, PHARE (https://xiazlab.org/phare/), which applies to both scRNA-seq and bulk RNA-seq data. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

immunology↗

bioRxiv2024

DNA damage drives antigen diversification through mosaic VSG formation in Trypanosoma brucei

Antigenic variation, using large genomic repertoires of antigen-encoding genes, allows pathogens to evade host antibody. Many pathogens, including the African trypanosome Trypanosoma brucei, extend their antigenic repertoire through genomic diversification. While evidence suggests that T. brucei depends on the generation of new variant surface glycoprotein (VSG) genes to maintain a chronic infection, a lack of experimentally tractable tools for studying this process has obscured its underlying mechanisms. Here, we present a highly sensitive targeted sequencing approach for measuring VSG diversification. Using this method, we demonstrate that a Cas9-induced DNA double-strand break within the VSG coding sequence can induce VSG recombination with patterns identical to those observed during infection. These newly generated VSGs are antigenically distinct from parental clones and thus capable of facilitating immune evasion. Together, these results provide insight into the mechanisms of VSG diversification and an experimental framework for studying the evolution of antigen repertoires in pathogenic microbes.

microbiology↗

bioRxiv2024

Illuminating the Dark Cancer Phosphoproteome Through a Machine-Learned Co-Regulation Map of 26,280 Phosphosites

Mass spectrometry-based phosphoproteomics offers a comprehensive view of protein phosphorylation, but limited knowledge about the regulation and function of most phosphosites restricts our ability to extract meaningful biological insights from phosphoproteomics data. To address this, we combine machine learning and phosphoproteomic data from 1,195 tumor specimens spanning 11 cancer types to construct CoPheeMap, a network mapping the co-regulation of 26,280 phosphosites. Integrating network features from CoPheeMap into a machine learning model, CoPheeKSA, we achieve superior performance in predicting kinase-substrate associations. CoPheeKSA reveals 24,015 associations between 9,399 phosphosites and 104 serine/threonine kinases, including many unannotated phosphosites and under-studied kinases. We validate the accuracy of these predictions using experimentally determined kinase-substrate specificities. By applying CoPheeMap and CoPheeKSA to phosphosites with high computationally predicted functional significance and cancer-associated phosphosites, we demonstrate the effectiveness of these tools in systematically illuminating phosphosites of interest, revealing dysregulated signaling processes in human cancer, and identifying under-studied kinases as putative therapeutic targets.

cancer biology↗

bioRxiv2024

A rapid and efficient in vivo inoculation method for introducing tree stem canker pathogens onto leaves, suitable for large-scale assessment of resistance in poplar breeding progeny

Hybrid breeding, a direct and efficient strategy for disease control and management in tree species, is currently limited by the selection method of resist clones: the "in vitro stem segment inoculation method." This method, constrained by the availability of inoculating materials, cannot rapidly, efficiently, and cost-effectively screen the resistance of all hybrid clones. To overcome these limitations, we introduce a novel pathogen inoculation method for the resistance assessment of hybrid clones in the poplar-Valsa sordida pathosystem. This method involves inoculating the stem canker pathogen on the host leaf, a unique and promising approach we have successfully validated. Results showed that stem canker pathogen V. sordida induced the extended necrotic lesion and even induced the formation of pycnidium structure and conidia on the leaf surface five days after mycelium inoculation; 1) the upper 5-7th leaves exhibited higher resistance than the middle 18-20th leaves; 2) the shading conditions induced more severe symptoms on the leaves than lighting conditions; 3) the juvenile mycelium inoculums (4-day-cultured) were more susceptible to poplar leaves than the old ones (7-day-cultured). Our results demonstrate the robustness of the "in vivo leaf inoculation method" in revealing the resistance differentiation in poplar hybrid clones. According to the leaf necrotic area disease index, we divided these poplar clones into seven different resistance groups. The resistance assessed by leaf assessment was validated in 15 selected poplar clones using the "in vitro stem segment inoculation method." Results showed that the effectiveness of these two methods was consistent. Moreover, the leaf inoculation method can be used to detect the pathogenicity diversity of the pathogen population of tree species. Compared to the conventional "in vitro stem segment inoculation method," the leaf method has the advantages of abundant inoculation materials, easy operation, rapid disease onset, and almost no adverse effect on the host. It is particularly suitable for the resistance screening of all progeny and the early (seedling) phenotypic selection of resistant poplar clones in poplar stem disease resistance breeding. The "in vivo leaf inoculation method" holds significant promise in poplar breeding, tree pathology, and molecular biology research on tree stem diseases.

plant biology↗

bioRxiv2024

A cryopreservation strategy for myoblast storage in paper-based scaffolds for inter-laboratory studies of skeletal muscle health

Three-dimensional tissue-engineered models are poised to facilitate understanding of skeletal muscle pathophysiology and identify novel therapeutic agents to improve muscle health. Adopting these culture models within the broader biology community is a challenge as many models involve complex methodologies and significant investments of time and resources to optimize manufacturing protocols. To alleviate this barrier, we developed a protocol with commercially available reagents to cryopreserve myoblasts in a 96-well compatible format that allows tissues to be transferred to users without expertise in 2D or 3D skeletal muscle cell culture. We validate that myoblasts encapsulated in a hydrogel and cryopreserved in paper-based scaffolds maintain cell viability, differentiation, and function via acetylcholine-induced transient calcium responses. Furthermore, we demonstrate successful shipping of myoblasts cryopreserved in paper-based scaffolds to intra-provincial and international collaborators who successfully thawed, cultured, and used the 3D muscle tissues. Finally, we confirm the application of our method to study muscle endogenous repair by seeding freshly isolated skeletal muscle stem cells to cryopreserved then differentiated and injured tissues, demonstrating expected responses to a known stimulator of muscle stem cell self-renewal, p38/{beta} MAPKi. Altogether, our 3D myoblast cryopreservation protocol offers broadened access of a complex skeletal muscle tissue model to the research community.

bioengineering↗

bioRxiv2024

Epstein-Barr Virus Orchestrates Spatial Reorganization and Immunomodulation within the Classic Hodgkin Lymphoma Tumor Microenvironment

Classic Hodgkin Lymphoma (cHL) is a tumor composed of rare malignant Hodgkin and Reed-Sternberg (HRS) cells nested within a T-cell rich inflammatory immune infiltrate. cHL is associated with Epstein-Barr Virus (EBV) in 25% of cases. The specific contributions of EBV to the pathogenesis of cHL remain largely unknown, in part due to technical barriers in dissecting the tumor microenvironment (TME) in high detail. Herein, we applied multiplexed ion beam imaging (MIBI) spatial pro-teomics on 6 EBV-positive and 14 EBV-negative cHL samples. We identify key TME features that distinguish between EBV-positive and EBV-negative cHL, including the relative predominance of memory CD8 T cells and increased T-cell dysfunction as a function of spatial proximity to HRS cells. Building upon a larger multi-institutional cohort of 22 EBV-positive and 24 EBV-negative cHL samples, we orthogonally validated our findings through a spatial multi-omics approach, coupling whole transcriptome capture with antibody-defined cell types for tu-mor and T-cell populations within the cHL TME. We delineate contrasting transcriptomic immunological signatures between EBV-positive and EBV-negative cases that differently impact HRS cell proliferation, tumor-immune interactions, and mecha-nisms of T-cell dysregulation and dysfunction. Our multi-modal framework enabled a comprehensive dissection of EBV-linked reorganization and immune evasion within the cHL TME, and highlighted the need to elucidate the cellular and molecular fac-tors of virus-associated tumors, with potential for targeted therapeutic strategies.

cancer biology↗

bioRxiv2024

Assessing the impact of Brd2 depletion on chromatin compartmentalization

Recent insights into genome organization have emphasized the importance of A/B chromatin compartments. While our previous research showed that Brd2 depletion weakens compartment boundaries and promotes A/B mixing 1, Hinojosa-Gonzalez et al.2 were unable to replicate the findings. In response, we revisited our Micro-C data and successfully replicated the original results using the default parameters in the cooltools software package. We show that, after correcting inconsistencies with the selection and phasing of the compartment profiles, the decrease in B compartment strength persists but the change in compartment identity is to a much lesser extent than originally reported. To further assess the regulatory role of Brd2, we used saddle plots to determine the strength of compartmentalization and observed a consistent decrease of compartment strength especially at B compartments upon Brd2 depletion. This study highlights the importance of selecting appropriate parameters and analytical tools for compartment analysis and carefully interpreting the results.

genomics↗

bioRxiv2024

Human brain aging heterogeneity observed from multi-region omics data reveals a subtype closely related to Alzheimer's disease

INTRODUCTION: The interconnection between brain aging and Alzheimers disease (AD) remain to be elucidated. METHODS: We investigated multi-omics (transcriptomics and proteomics) data from multiple brain regions (i.e., the hippocampus (HIPP), prefrontal cortex (PFC), and cerebellum (CRBL)) in cognitively normal individuals. RESULTS: We found that brain samples could be divided into ADL (AD-like) and NL (normal) subtypes which were correlated across brain regions. The differentially expressed genes in the ADL samples highly overlapped with AD gene signatures and the changes were consistent across brain regions (PFC and HIPP) in the multi-omics data. Intriguingly, the ADL subtype in PFC showed more differentially expressed genes than other brain regions, which could be explained by the baseline gene expression differences in the PFC NL samples. DISCUSSION: We conclude that brain aging heterogeneity widely exists, and our findings corroborate with the hypothesis that AD-related changes occur decades before the clinical manifestation of cognitive impairment in a sub-population.

neuroscience↗