Differential DNA Methylation Associated with Multiple Sclerosis in an Underrepresented Population and Disease Modifying Treatments in an Underrepresented Minority Population
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PROVIDER: PRJNA907873 | ENA |
REPOSITORIES: ENA
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Project description:Black and Hispanic American patients frequently develop earlier onset of multiple sclerosis (MS) and a more severe disease course that can be resistant to disease modifying treatments. The objectives were to identify differential methylation of genomic DNA (gDNA) associated with disease susceptibility and treatment responses in a cohort of MS patients from underrepresented minority populations. Patients with MS and controls with non-inflammatory neurologic conditions were consented and enrolled under an IRB-approved protocol. Approximately 64% of donors identified as Black or African American and 30% as White, Hispanic-Latino. Infinium MethylationEPIC bead arrays were utilized to measure epigenome-wide gDNA methylation of whole blood. Data were analyzed in the presence and absence of adjustments for unknown covariates in the dataset, some of which corresponded to disease modifying treatments. Global patterns of differential methylation associated with MS were strongest for those probes that showed relative demethylation of loci with lower M values. Pathway analysis revealed unexpected associations with shigellosis and amoebiasis. Enrichment analysis revealed an over-representation of probes in enhancer regions and an under-representation in promoters. In the presence of adjustments for covariates that included disease modifying treatments, analysis revealed 10 differentially methylated regions (DMR’s) with an FDR <1E-77. Five of these genes (ARID5B, BAZ2B, RABGAP1, SFRP2, WBP1L) are associated with cancer risk and cellular differentiation and have not been previously identified in MS studies. Hierarchical cluster and multi-dimensional scaling analysis of differential DNA methylation at 147 loci within those DMR’s was sufficient to differentiate MS donors from controls. In the absence of corrections for disease modifying treatments, differential methylation in patients treated with dimethyl fumarate was associated with immune regulatory pathways that regulate cytokine and chemokine signaling, axon guidance, and adherens junctions. These results demonstrate possible associations of gastrointestinal pathogens and regulation of cellular differentiation with MS susceptibility in our patient cohort. This work further suggests that analyses can be performed in the presence and absence of corrections for immune therapies. Because of their high representation in our patient cohort, these results may be of specific relevance in the regulation of disease susceptibility and treatment responses in Black and Hispanic Americans.
2023-02-07 | GSE219293 | GEO
Project description:Black and Hispanic American patients frequently develop earlier onset of multiple sclerosis (MS) and a more severe disease course that can be resistant to disease modifying treatments. The objectives were to identify differential methylation of genomic DNA (gDNA) associated with disease susceptibility and treatment responses in a cohort of MS patients from underrepresented minority populations. Patients with MS and controls with non-inflammatory neurologic conditions were consented and enrolled under an IRB-approved protocol. Approximately 64% of donors identified as Black or African American and 30% as White, Hispanic-Latino. Infinium MethylationEPIC bead arrays were utilized to measure epigenome-wide gDNA methylation of whole blood. Data were analyzed in the presence and absence of adjustments for unknown covariates in the dataset, some of which corresponded to disease modifying treatments. Global patterns of differential methylation associated with MS were strongest for those probes that showed relative demethylation of loci with lower M values. Pathway analysis revealed unexpected associations with shigellosis and amoebiasis. Enrichment analysis revealed an over-representation of probes in enhancer regions and an under-representation in promoters. In the presence of adjustments for covariates that included disease modifying treatments, analysis revealed 10 differentially methylated regions (DMR's) with an FDR <1E-77. Five of these genes (ARID5B, BAZ2B, RABGAP1, SFRP2, WBP1L) are associated with cancer risk and cellular differentiation and have not been previously identified in MS studies. Hierarchical cluster and multi-dimensional scaling analysis of differential DNA methylation at 147 loci within those DMR's was sufficient to differentiate MS donors from controls. In the absence of corrections for disease modifying treatments, differential methylation in patients treated with dimethyl fumarate was associated with immune regulatory pathways that regulate cytokine and chemokine signaling, axon guidance, and adherens junctions. These results demonstrate possible associations of gastrointestinal pathogens and regulation of cellular differentiation with MS susceptibility in our patient cohort. This work further suggests that analyses can be performed in the presence and absence of corrections for immune therapies. Because of their high representation in our patient cohort, these results may be of specific relevance in the regulation of disease susceptibility and treatment responses in Black and Hispanic Americans.
| S-EPMC9845287 | biostudies-literature
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Project description:The response of human immunodeficiency virus type 1 (HIV-1) quasispecies to antiretroviral therapy is influenced by the ensemble of mutants that composes the evolving population. Low-abundance subpopulations within HIV-1 quasispecies may determine the viral response to the administered drug combinations. However, routine sequencing assays available to clinical laboratories do not recognize HIV-1 minority variants representing less than 25% of the population. Although several alternative and more sensitive genotyping techniques have been developed, including next-generation sequencing (NGS) methods, they are usually very time consuming, expensive and require highly trained personnel, thus becoming unrealistic approaches in daily clinical practice. Here we describe the development and testing of a HIV-1 genotyping DNA microarray that detects and quantifies, in majority and minority viral subpopulations, relevant mutations and amino acid insertions in 42 codons of the pol gene associated with resistance and multidrug resistance to protease (PR) and reverse transcriptase (RT) inhibitors. A customized bioinformatics protocol has been implemented to analyze the microarray hybridization data by including a new normalization procedure and a stepwise filtering algorithm which resulted in the highly accurate (96.33%) detection of positive/negative signals. This microarray has been tested with 57 subtype B HIV-1 clinical samples extracted from multi-treated patients, showing an overall identification of 95.53% and 89.24% of the queried PR and RT codons, respectively, and enough sensitivity to detect minority subpopulations representing as low as 5-10% of the total quasispecies. Such a genotyping platform represents an efficient diagnostic and prognostic tool useful to personalize antiviral treatments in clinical practice.
2016-11-30 | GSE90621 | GEO
Project description:Metastasis is responsible for the majority of cancer-related deaths1. Although single-cell RNA sequencing (scRNA-seq) has revealed considerable heterogeneity among tumor cells, identifying the cellular determinants of metastasis has remained challenging. Here, we analyzed scRNA-seq data of primary human breast tumor biopsies and identified a minority population of immature THY1+/VEGFA+ basal epithelial cells that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher levels of LMO2+ basal cells in human breast tumors correlated with endothelial content and predicted poor distant recurrence-free survival. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrate that Lmo2 lineage-traced cells integrate into the vasculature and metastasize to the lung. In human breast tumors, knockdown of LMO2 reduced lung metastasis by affecting multiple steps required for intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 is a binding partner of STAT3 and is required for STAT3 activation in the presence of the inflammatory cytokines, TNFα and IL6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.
2023-10-08 | GSE159284 | GEO
Project description:Metastasis is responsible for the majority of cancer-related deaths1. Although single-cell RNA sequencing (scRNA-seq) has revealed considerable heterogeneity among tumor cells, identifying the cellular determinants of metastasis has remained challenging. Here, we analyzed scRNA-seq data of primary human breast tumor biopsies and identified a minority population of immature THY1+/VEGFA+ basal epithelial cells that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher levels of LMO2+ basal cells in human breast tumors correlated with endothelial content and predicted poor distant recurrence-free survival. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrate that Lmo2 lineage-traced cells integrate into the vasculature and metastasize to the lung. In human breast tumors, knockdown of LMO2 reduced lung metastasis by affecting multiple steps required for intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 is a binding partner of STAT3 and is required for STAT3 activation in the presence of the inflammatory cytokines, TNFα and IL6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.
2023-10-08 | GSE159282 | GEO
Project description:Drugs that target pre-mRNA splicing hold great therapeutic potential, but the mechanistic understanding of how these drugs function is limited. Here we introduce a biophysical modeling framework that can quantitatively describe the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we apply this framework to two drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively define the specificities of risdiplam and branaplam for 5’ splice site sequences, suggest that branaplam recognizes 5’ splice sites via two distinct interaction modes, and disprove the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show, more generally, that single-drug cooperativity and multi-drug synergy are widespread among splice-modifying drugs. Our biophysical modeling approach thus clarifies the mechanisms of existing splice-modifying treatments and provides a quantitative basis for the rational development of new therapies.
2023-01-09 | GSE221868 | GEO
Project description:Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.
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Project description:Identification of a minority population in breast cancer that integrates into the vasculature and initiates metastasis [scRNA-Seq]
| PRJNA668295 | ENA
Project description:Identification of a minority population in breast cancer that integrates into the vasculature and initiates metastasis. [RNA-seq]
| PRJNA668284 | ENA