The effect of exposure to neighborhood violence on GR signaling in lung tumors [CUT&Run]
Ontology highlight
ABSTRACT: Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to White men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in lung tumor samples in relation to GR target gene expression levels and zip code level residential neighborhood violence. Spatial transcriptomics and a version of ChIP-sequencing known as CUT & RUN were used. GR recruitment to chromatin was correlated with neighborhood violent crime rate and overall GR binding increased with increasing neighborhood violent crime rates. Among patients residing in high-violence neighborhoods, tumor samples, compared to normal neighboring lung tissue, had fewer GR binding sites. The opposite was seen in patients residing in low-violence neighborhoods, with tumor samples having more GR binding sites when compared to normal lung tissue. Tumor samples from patients living in high-violence neighborhoods exhibited increased GR recruitment to genes associated with greater tumor aggressiveness. Our findings suggest that exposure to neighborhood violence may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high violence, may reduce racial disparities in lung cancer.
Project description:Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to White men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in lung tumor samples in relation to GR target gene expression levels and zip code level residential neighborhood violence. Spatial transcriptomics and a version of ChIP-sequencing known as CUT & RUN were used. GR recruitment to chromatin was correlated with neighborhood violent crime rate and overall GR binding increased with increasing neighborhood violent crime rates. Among patients residing in high-violence neighborhoods, tumor samples, compared to normal neighboring lung tissue, had fewer GR binding sites. The opposite was seen in patients residing in low-violence neighborhoods, with tumor samples having more GR binding sites when compared to normal lung tissue. Tumor samples from patients living in high-violence neighborhoods exhibited increased GR recruitment to genes associated with greater tumor aggressiveness. Our findings suggest that exposure to neighborhood violence may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high violence, may reduce racial disparities in lung cancer.
Project description:Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ. Mouse lungs follow stereotyped sequences of fibrogenesis-to-resolution after bleomycin injury, and we reasoned that profiling post-injury histological progression could uncover pro- vs. anti-fibrotic features with functional value for human fibrosis. We mapped spatiotemporally-resolved transformations in lung extracellular matrix (ECM) architecture to spatially-resolved, multi-omic data. First, we charted stepwise trajectories of matrix aberration vs. resolution using unsupervised machine learning, denoting a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally-enriched “ECM-secreting” (Csmd1+) and “pro-resolving” (Cd248+) fibroblasts, for which Visium inferred divergent histological signatures and spatial-transcriptional “neighborhoods”. Critically, pro-resolving fibroblast instillation helped ameliorate fibrosis in vivo. Further, fibroblast neighborhood-associated moieties, Serpine2 and Pi16, functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis further uncovered analogous fibroblast subtypes and neighborhoods in human disease. Collectively, these findings establish an atlas of pro-/anti-fibrotic factors underlying lung matrix architecture and implicate fibroblast-centered moieties in modulating fibrotic progression vs. resolution.
Project description:Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ. Mouse lungs follow stereotyped sequences of fibrogenesis-to-resolution after bleomycin injury, and we reasoned that profiling post-injury histological progression could uncover pro- vs. anti-fibrotic features with functional value for human fibrosis. We mapped spatiotemporally-resolved transformations in lung extracellular matrix (ECM) architecture to spatially-resolved, multi-omic data. First, we charted stepwise trajectories of matrix aberration vs. resolution using unsupervised machine learning, denoting a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally-enriched “ECM-secreting” (Csmd1+) and “pro-resolving” (Cd248+) fibroblasts, for which Visium inferred divergent histological signatures and spatial-transcriptional “neighborhoods”. Critically, pro-resolving fibroblast instillation helped ameliorate fibrosis in vivo. Further, fibroblast neighborhood-associated moieties, Serpine2 and Pi16, functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis further uncovered analogous fibroblast subtypes and neighborhoods in human disease. Collectively, these findings establish an atlas of pro-/anti-fibrotic factors underlying lung matrix architecture and implicate fibroblast-centered moieties in modulating fibrotic progression vs. resolution.
Project description:Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ. Mouse lungs follow stereotyped sequences of fibrogenesis-to-resolution after bleomycin injury, and we reasoned that profiling post-injury histological progression could uncover pro- vs. anti-fibrotic features with functional value for human fibrosis. We mapped spatiotemporally-resolved transformations in lung extracellular matrix (ECM) architecture to spatially-resolved, multi-omic data. First, we charted stepwise trajectories of matrix aberration vs. resolution using unsupervised machine learning, denoting a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally-enriched “ECM-secreting” (Csmd1+) and “pro-resolving” (Cd248+) fibroblasts, for which Visium inferred divergent histological signatures and spatial-transcriptional “neighborhoods”. Critically, pro-resolving fibroblast instillation helped ameliorate fibrosis in vivo. Further, fibroblast neighborhood-associated moieties, Serpine2 and Pi16, functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis further uncovered analogous fibroblast subtypes and neighborhoods in human disease. Collectively, these findings establish an atlas of pro-/anti-fibrotic factors underlying lung matrix architecture and implicate fibroblast-centered moieties in modulating fibrotic progression vs. resolution.
Project description:Social determinants of health influence health outcomes and life expectancy. Specifically, individuals living in poverty often have adverse health outcomes related to chronic inflammation that affect the cardiovascular, renal, and pulmonary systems. However, the underlying mechanisms by which poverty increases the risk of disease and health disparities are still not fully understood. To bridge the gap in our understanding of the link between living in poverty and adverse health outcomes, we performed RNA sequencing of blood immune cells from 204 participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study in Baltimore City, Maryland. This study cohort included men and women self-identified as African American and White. We identified genes differentially expressed in association with poverty. Our results suggest that living in poverty influences inflammation and the risk for chronic disease through gene expression changes in immune cells, and that some of the effects of living in poverty are different in women and men.
Project description:How steroid hormone receptors (SHRs) orchestrate transcriptional activity remains only partly understood. Upon activation, SHRs bind the genome and recruit their co-regulators, crucial to induce gene expression. However, it remains unknown which components of the SHR-recruited coregulator complex are essential to drive transcription following hormonal stimuli. Through a FACS-based genome-wide CRISPR screen, we comprehensively dissected the Glucocorticoid Receptor (GR) co-regulatory complex involved in gene-target regulation. We describe a novel functional cross-talk between PAXIP1 and the cohesin subunit STAG2 that is critical for regulation of gene expression by GR. Without altering the GR cistrome, PAXIP1 and STAG2 depletion alter the GR transcriptome, by impairing the recruitment of 3D-genome organization proteins to the GR complex. Importantly, we demonstrate that PAXIP1 is required for stability of cohesin on the genome, its localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. Moreover, in lung cancer, where GR acts as tumor suppressor, PAXIP1/STAG2 loss enhances GR-mediated tumor suppressor activity by modifying local chromatin interactions. All together, we introduce PAXIP1 and STAG2 as novel co-regulators of GR, required to maintain 3D-genome architecture and drive the GR transcriptional programme following hormonal stimuli.
Project description:Lung cancer is the single most frequent cause of cancer death worldwide and is relatively more common in males. For reasons that are currently unknown, lung cancer is also associated with significantly worse outcomes in men than women. Here we replicate clustering of Y-chromosome transcripts identified previously as showing tumor-specific disruption in men with lung cancer.
Project description:Prostate cancer incidence and related mortality are disproportionately higher in African American (AA) men than European American (EA) men, but the molecular mechanisms contributing to racial disparities are not fully elucidated. To identify molecular factors that can contribute to disease biology in prostate cancer from AA and EA men, we utilized a multi-omics approach to measure and integrate DNA methylation with gene expression changes. We compared and contrasted results from adjacent non-tumor and tumor tissues from AA and EA men. We found that hypermethylated regions are enriched for PRC2 and H3K27me3 pathways and EZH2/SUZ12 cofactors in a race-independent manner. On the other hand, hypomethylated regions in prostate tumors from AA men were enriched for olfactory/ribosomal pathways as well as distinct cofactors such as CTCF and KMT2A. DNA methylation at transcription start sites and 5’-UTR at GATA3, an androgen receptor (AR) coregulator, is associated with decreased gene expression in prostate tumors of AA men. Our analysis also showed an inverse correlation between DNA methylation and RNA expression of AR transcriptional targets, such as TRIM63, in prostate tumors of AA men. Our observations suggest a dysregulation of the AR signaling pathway in prostate cancer from AA men. To determine whether targeting AR results in race-specific gene expression changes, we utilized a prostate-cancer-specific Boolean network. Our simulation revealed that prolonged AR inhibition results in significant dysregulation in TGF-β, IDH1, and cell cycle pathways in prostate cancer of AA men. We expanded our observation of gene expression changes in the Boolean network and investigated RNA-sequencing data to better understand overall transcriptional alterations occurring in prostate tumors from AA and EA men. We found that gene expression changes related to microtubules, a subset of immune-related, and TMPRSS2-fusion pathways were dysregulated in prostate tumors of AA men and corresponded with progression-free survival of AA men. Altogether, the current study dissects complex signaling networks that are clinically actionable in prostate cancer from AA and EA men.