Crosstalk between RNA-Binding Proteins and Immune Microenvironment Revealed Two RBP Regulatory Patterns with Distinct Immunophenotypes in Periodontitis.
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ABSTRACT:
SUBMITTER: Xing L
PROVIDER: S-EPMC8275429 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and immune regulation in colorectal cancer (CRC) remains unclear. Methods Ten cuprotosis-related genes were selected and unsupervised consensus clustering was performed to identify the cuprotosis patterns and the correlated TME characteristics. Using principal component analysis, a COPsig score was established to quantify cuprotosis patterns in individual patients. The top 9 most important cuprotosis signature genes were analyzed using single-cell transcriptome data. Results Three distinct cuprotosis patterns were identified. The TME cell infiltration characteristics of three patterns were associated with immune-excluded, immune-desert, and immune-inflamed phenotype, respectively. Based on individual cuprotosis patterns, patients were assigned into high and low COPsig score groups. Patients with a higher COPsig score were characterized by longer overall survival time, lower immune cell as well as stromal infiltration, and greater tumor mutational burden. Moreover, further analysis demonstrated that CRC patients with a higher COPsig score were more likely to respond to immune checkpoint inhibitors and 5-fluorouracil chemotherapy. Single-cell transcriptome analysis indicated that cuprotosis signature genes recruited tumor-associated macrophages to TME through the regulation of TCA and the metabolism of glutamine and fatty acid, thus influencing the prognosis of CRC patients. Conclusion This study indicated that distinct cuprotosis patterns laid a solid foundation to the explanation of heterogeneity and complexity of individual TME, thus guiding more effective immunotherapy as well as adjuvant chemotherapy strategies.
| S-EPMC10060625 | biostudies-literature
Project description:The detection and characterization of binding pockets and allosteric communication in proteins is crucial for studying biological regulation and performing drug design. Nowadays, ever-longer molecular dynamics (MD) simulations are routinely used to investigate the spatiotemporal evolution of proteins. Yet, there is no computational tool that can automatically detect all the pockets and potential allosteric communication networks along these extended MD simulations. Here, we use a novel and fully automated algorithm that examines pocket formation, dynamics, and allosteric communication embedded in microsecond-long MD simulations of three pharmaceutically relevant proteins, namely, PNP, A2A, and Abl kinase. This dynamic analysis uses pocket crosstalk, defined as the temporal exchange of atoms between adjacent pockets, along the MD trajectories as a fingerprint of hidden allosteric communication networks. Importantly, this study indicates that dynamic pocket crosstalk analysis provides new mechanistic understandings on allosteric communication networks, enriching the available experimental data. Thus, our results suggest the prospective use of this unprecedented dynamic analysis to characterize transient binding pockets for structure-based drug design.
| S-EPMC5620967 | biostudies-literature
Project description:Despite increasing evidence that antitumor immune control exists in the pediatric brain, these findings have yet to be exploited successfully in the clinic. A barrier to development of immunotherapeutic strategies in pediatric brain tumors is that the immunophenotype of these tumors' microenvironment has not been defined. To address this, the current study used multicolor FACS of disaggregated tumor to systematically characterize the frequency and phenotype of infiltrating immune cells in the most common pediatric brain tumor types. The initial study cohort consisted of 7 pilocytic astrocytoma (PA), 19 ependymoma (EPN), 5 glioblastoma (GBM), 6 medulloblastoma (MED), and 5 nontumor brain (NT) control samples obtained from epilepsy surgery. Immune cell types analyzed included both myeloid and T cell lineages and respective markers of activated or suppressed functional phenotypes. Immune parameters that distinguished each of the tumor types were identified. PA and EPN demonstrated significantly higher infiltrating myeloid and lymphoid cells compared with GBM, MED, or NT. Additionally, PA and EPN conveyed a comparatively activated/classically activated myeloid cell-skewed functional phenotype denoted in particular by HLA-DR and CD64 expression. In contrast, GBM and MED contained progressively fewer infiltrating leukocytes and more muted functional phenotypes similar to that of NT. These findings were recapitulated using whole tumor expression of corresponding immune marker genes in a large gene expression microarray cohort of pediatric brain tumors. The results of this cross-tumor comparative analysis demonstrate that different pediatric brain tumor types exhibit distinct immunophenotypes, implying that specific immunotherapeutic approaches may be most effective for each tumor type.
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Project description:The relationship between autophagy and immunity has been thoroughly investigated. However, little is known about the role of autophagy in shaping the immune-microenvironment of periodontitis. Thus, we aim to explore the impact of autophagy on the immune-microenvironment of periodontitis. The expression distinctions of autophagy genes between healthy and periodontitis samples have been investigated. The connections between autophagy and immune characteristics including infiltrating immunocyte, immune reaction and human leukocyte antigen (HLA) gene were evaluated. The distinct autophagy-mediated expression patterns were identified and immune characteristics under distinct patterns were revealed. Autophagy phenotype-related genes were identified. 16 autophagy genes were dysregulated and a ten-autophagy classifier was constructed that can well distinguish periodontitis and healthy samples. Immune characteristics were closely related to autophagy: higher expression of EDEM1 positively relates to infiltrating activated B cell; NCKAP1 negatively relates to monocyte; CXCR4 enhances BCR Signaling Pathway and PEX3 decreases the activity of TNF Family Members Receptors; positive expression correlation of EDEM1-HLADOB and negative correlation of RAB11A-HLADOB were observed. Two distinct autophagy expression patterns were identified which demonstrated different immune characteristics. 4309 autophagy phenotype-related genes were identified, and 219 of them were related to immunity, whose biological functions were found to be involved in immunocyte regulations. Our study revealed the strong impact of autophagy on the immune-microenvironment of periodontitis and brought new insights into the understanding of the pathogenesis of periodontitis.
| S-EPMC7835039 | biostudies-literature
Project description:Periodontitis has a polymicrobial etiology within the framework of a complex microbial ecosystem. With advances in sequencing technologies, comprehensive studies to elucidate bacterial community differences have recently become possible. We used 454 sequencing of 16S rRNA genes to compare subgingival bacterial communities from 29 periodontally healthy controls and 29 subjects with chronic periodontitis. Amplicons from both the V1-2 and V4 regions of the 16S gene were sequenced, yielding 1,393,579 sequences. They were identified by BLAST against a curated oral 16S database, and mapped to 16 phyla, 106 genera, and 596 species. 81% of sequences could be mapped to cultivated species. Differences between health- and periodontitis-associated bacterial communities were observed at all phylogenetic levels, and UniFrac and principal coordinates analysis showed distinct community profiles in health and disease. Community diversity was higher in disease, and 123 species were identified that were significantly more abundant in disease, and 53 in health. Spirochaetes, Synergistetes and Bacteroidetes were more abundant in disease, whereas the Proteobacteria were found at higher levels in healthy controls. Within the phylum Firmicutes, the class Bacilli was health-associated, whereas the Clostridia, Negativicutes and Erysipelotrichia were associated with disease. These results implicate a number of taxa that will be targets for future research. Some, such as Filifactor alocis and many Spirochetes were represented by a large fraction of sequences as compared with previously identified targets. Elucidation of these differences in community composition provides a basis for further understanding the pathogenesis of periodontitis.
| S-EPMC3358035 | biostudies-literature
Project description:The role of epigenetic regulation in immunity is emerging, especially for RNA N6-methyladenosine (m6A) modification. However, little is known about the role of m6A in the regulation of the immune microenvironment of periodontitis. Thus, we aim to investigate the impact of m6A modification in periodontitis immune microenvironment. The RNA modification patterns mediated by 23 m6A-regulators were systematically evaluated in 310 periodontitis samples. The impact of m6A modification on immune microenvironment characteristics was explored, including infiltrating immunocytes, immune reaction gene-sets and HLAs (human leukocyte antigen) gene. m6A phenotype-related immune genes were also identified. 17 m6A regulators were dysregulated and a 15-m6A regulator signature can well distinguish periodontitis and control samples. ALKBH5 and FMR1 are closely related to infiltrating monocyte abundance. ELAVL1 and CBLL1 are significant regulators in immune reaction of TNF_Family_Members_Receptors and Cytokine. The expression of HLA-B and HLA-DOA is affected by ALKBH5 and LRPPRC. 3 distinct RNA modification patterns mediated by 23 m6A regulators were identified. They differ from immunocyte abundance, immune reaction and HLA gene. 1631 m6A phenotype-related genes and 70 m6A-mediated immune genes were identified, and the biological functions of these were explored. Our finding demonstrated the m6A modification plays a crucial role in the diversity and complexity of the immune microenvironment of periodontitis.
| S-EPMC8034465 | biostudies-literature
Project description:The coordination of the synthesis of functionally-related proteins can be achieved at the post-transcriptional level by the action of common regulatory molecules, such as RNA-binding proteins (RBPs). Despite advances in the genome-wide identification of RBPs and their binding transcripts, the protein-RNA interaction space is still largely unexplored, thus hindering a broader understanding of the extent of the post-transcriptional regulation of related coding RNAs. Here, we propose a computational approach that combines protein-mRNA interaction networks and statistical analyses to provide an inferred regulatory landscape for more than 800 human RBPs and identify the cellular processes that can be regulated at the post-transcriptional level. We show that 10% of the tested sets of functionally-related mRNAs can be post-transcriptionally regulated. Moreover, we propose a classification of (i) the RBPs and (ii) the functionally-related mRNAs, based on their distinct behaviors in the functional landscape, hinting towards mechanistic regulatory hypotheses. In addition, we demonstrate the usefulness of the inferred functional landscape to investigate the cellular role of both well-characterized and novel RBPs in the context of human diseases.
| S-EPMC6416249 | biostudies-literature
Project description:Alternative splicing of pre-messenger RNA transcripts enables the generation of multiple protein isoforms from the same gene locus, providing a major source of protein diversity in mammalian genomes. RNA binding proteins (RBPs) bind to RNA to control splice site choice and define which exons are included in the resulting mature RNA transcript. However, depending on where the RBPs bind relative to splice sites, they can activate or repress splice site usage. To explore this position-specific regulation, in vivo binding sites identified by methods such as cross-linking and immunoprecipitation (CLIP) are integrated with alternative splicing events identified by RNA-seq or microarray. Merging these data sets enables the generation of a "splicing map," where CLIP signal relative to a merged meta-exon provides a simple summary of the position-specific effect of binding on splicing regulation. Here, we provide RBP-Maps, a software tool to simplify generation of these maps and enable researchers to rapidly query regulatory patterns of an RBP of interest. Further, we discuss various alternative approaches to generate such splicing maps, focusing on how decisions in construction (such as the use of peak versus read density, or whole-reads versus only single-nucleotide candidate crosslink positions) can affect the interpretation of these maps using example eCLIP data from the 150 RBPs profiled by the ENCODE consortium.
| S-EPMC6348990 | biostudies-literature
Project description:BACKGROUND. Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited. METHODS. We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC). RESULTS. Cytometric profiling identified an immunologically "hot" cluster with abundant CD8+ T cells expressing high levels of PD-1 and TIM-3 and an immunologically "cold" cluster with lower relative abundance of CD8+ T cells and expression of inhibitory markers. The "hot" cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the "hot" cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10. CONCLUSIONS. Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer. FUNDING. The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.
| S-EPMC5033841 | biostudies-literature
Project description:BackgroundSevere acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causes direct lung damage, overwhelming endothelial activation, and inflammatory reaction, leading to acute respiratory failure and multi-organ dysfunction. Ongoing clinical trials are evaluating targeted therapies to hinder this exaggerated inflammatory response. Critically ill coronavirus disease 2019 (COVID-19) patients have shown heterogeneous severity trajectories, suggesting that response to therapies is likely to vary across patients.Research questionAre critically ill COVID-19 patients biologically and immunologically dissociable based on profiling of currently evaluated therapeutic targets?Study design and methodsWe did a single-center, prospective study in an ICU department in France. Ninety-six critically ill adult patients admitted with a documented SARS-CoV-2 infection were enrolled. We conducted principal components analysis and hierarchical clustering on a vast array of immunologic variables measured on the day of ICU admission.ResultsWe found that patients were distributed in three clusters bearing distinct immunologic features and associated with different ICU outcomes. Cluster 1 had a "humoral immunodeficiency" phenotype with predominant B-lymphocyte defect, relative hypogammaglobulinemia, and moderate inflammation. Cluster 2 had a "hyperinflammatory" phenotype, with high cytokine levels (IL-6, IL-1β, IL-8, tumor necrosis factor-alpha [TNF⍺]) associated with CD4+ and CD8+ T-lymphocyte defects. Cluster 3 had a "complement-dependent" phenotype with terminal complement activation markers (elevated C3 and sC5b-9).InterpretationPatients with severe COVID-19 exhibiting cytokine release marks, complement activation, or B-lymphocyte defects are distinct from each other. Such immunologic variability argues in favor of targeting different mediators in different groups of patients and could serve as a basis for patient identification and clinical trial eligibility.
| S-EPMC7831685 | biostudies-literature