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Differential transcriptional responses of murine alveolar macrophages to elongated mineral particles of asbestiform and non-asbestiform varieties

ABSTRACT: Occupational exposures to asbestiform elongated mineral particles (EMPs) may lead to diffuse fibrosis, lung cancer, malignant mesothelioma and autoimmune diseases. Cleavage fragments (CF) are chemically identical to asbestiform varieties of parent mineral, but there is no consensus on whether to treat them as asbestos from toxicological and regulatory standpoints. Alveolar macrophages (AM) are the first-responders to inhaled particulates, participating in clearance, and activating the other resident and recruited immunocompetent cells, which has an impact on the long-term outcomes. In the current study we addressed the question of how asbestiform vs. non-asbestiform EMPs affect AM responses. Max Planck Institute (MPI) cells, a non-transformed mouse line that has AM phenotype and genotype, were treated with surface area-equivalent concentrations of respirable asbestiform and non-asbestiform riebeckite/tremolite EMPs for 24h. Detectable changes in macrophage gene expression happen within 6-24 hours post-stimuli (Schneider et al., 2019), thus we performed the next generation RNA sequencing of the MPI cells 24 hours post exposure to surface area-equivalent doses of riebeckite and tremolite EMPs to see if AM immediate transcriptional reprogramming patterns are intrinsic for different minerals and/or crystallization habit.

ORGANISM(S): Mus musculus

PROVIDER: GSE157922 | GEO | 2021/09/01

REPOSITORIES: GEO

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Project description:Background: Accurate survival stratification in early-stage NSCLC could inform the use of adjuvant therapy. We developed a clinically-implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables. Methods: Gene expression profiles from 1106 non-squamous NSCLCs were used for generation and internal validation of a 9-gene molecular prognostic index (MPI). Expression of the MPI genes was determined within sorted tumor cell subpopulations. A quantitative PCR (qPCR) assay was developed and validated on an independent cohort of FFPE tissues. A prognostic score using clinical variables was generated using Surveillance Epidemiology and End Results (SEER) data and combined with the MPI. Results: The MPI stratified stage I patients into prognostic categories in four independent validation datasets, including three microarray and one FFPE qPCR cohorts (HR=2.4, 95% CI, 1.8-3.3, P=7x10-9 in the largest microarray cohort; and HR=2.5, 95% CI 1.1-6.0, P=.03 in stage I patients of the qPCR validation cohort). Prognostic genes were expressed in distinct tumor cell subpopulations and expression of genes implicated in cellular proliferation and stem cells portended poor outcomes, while expression of genes involved in normal lung differentiation and immune infiltration was associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR=3.3, 95% CI 2.4-4.6; P=2x10-15 in the largest microarray cohort; and HR=3.6, 95% CI 1.5-8.8, P=.003 in stage I patients of the qPCR validation cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK. Conclusion: The MPI incorporates genes expressed in the tumor and its microenvironment, and designates risk of death for patients with early-stage non-squamous NSCLC. The MPI can be implemented clinically using qPCR assays on FFPE tissues and a composite model integrating the MPI with clinical variables provides the most accurate risk stratification.

Project description:Like human speech, birdsong is a complex vocal behavior that is acquired by sensorimotor learning based on coordination of auditory input and vocal output to mimic memorized tutor song. Here we investigate neural circuits for vocal learning and production in deafened songbirds to elucidate how sensory-input regulate genetic and epigenetic property of vocal development and its associated gene expression dynamics. Compared with audition-intact birds, in deafened zebra finches, the vocal development is delayed but song crystallization is observed at more than three times later, producing individually different but structured vocal patterns. In contrast to the distinct difference of vocal ontogeny between audition (+) and (-), unexpectedly, developmental regulation of gene expression dynamics is strictly conserved with age-locked trend in vocal motor circuit in both intact and deafened birds, indicating sensory-input independent robustness of developmental gene expression dynamics in the motor circuit for sensorimotor learning. This discrepancy between outward vocal phenotype and inward gene expression dynamics provides new insight into neural regulation at closing of the critical period for vocal learning by two different forms: auditory inputs-dependent M-bM-^@M-^XactiveM-bM-^@M-^Y crystallization and gene expression dynamics-mediated M-bM-^@M-^XpassiveM-bM-^@M-^Y crystallization. We collected brain samples from intact and early-deafened birds (deafened at day-post hatch 17-23) under silent and dark condition. Song nuclei in vocal motor circuit, HVC and RA tissue samples (juvenile; n = 3, young; n = 3, old; n = 3 of intact and early-deafened birds for HVC and RA) were laser-microdissected from total 24 birds (intact; n = 12, early-deafened; n = 12). Each sample was hybridized to a single array, totaling 36 arrays. Birds were selected per slide such that early-deafened birds were paired with intact birds. To minimize possible interslide bias or batch effects, intact and early-deafened bird samples matching with brain area and age conditions were hybridized side by side on same array glass.

Project description:modENCODE_submission_3217 This submission comes from a modENCODE project of Michael Snyder. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We are identifying the DNA binding sites for 300 transcription factors in C. elegans. Each transcription factor gene is tagged with the same GFP fusion protein, permitting validation of the gene's correct spatio-temporal expression pattern in transgenic animals. Chromatin immunoprecipitation on each strain is peformed using an anti-GFP antibody, and any bound DNA is deep-sequenced using Solexa GA2 technology. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-seq. BIOLOGICAL SOURCE: Strain: OP215(official name : OP215 genotype : unc119(ed3);wgIs215(W03F9.2::TY1 EGFP FLAG;unc119) outcross : 0 mutagen : None tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for bombardment transformation of an unc-119(ed3) strain. The W03F9.2::EGFP fusion protein is mainly expressed in germline cells. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the W03F9.2 transcription factor. made_by : Tony Hyman's lab from MPI-CBG ); Developmental Stage: L4-Young Adult; Genotype: unc119(ed3);wgIs215(W03F9.2::TY1 EGFP FLAG;unc119); Sex: Hermaphrodite; EXPERIMENTAL FACTORS: Developmental Stage L4-Young Adult; Target gene W03F9.2; Strain OP215(official name : OP215 genotype : unc119(ed3);wgIs215(W03F9.2::TY1 EGFP FLAG;unc119) outcross : 0 mutagen : None tags : GFP::3xFlag description : This strain's transgene was constructed by Mihail Sarov at the Max Planck Institute for Cell Biology in Tubiginen using Tony Hyman's recombineering pipeline. The resulting plasmid was used for bombardment transformation of an unc-119(ed3) strain. The W03F9.2::EGFP fusion protein is mainly expressed in germline cells. This strain was used for ChIP-seq experiments to map the in vivo binding sites for the W03F9.2 transcription factor. made_by : Tony Hyman's lab from MPI-CBG ); temp (temperature) 20 degree celsius

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Differential transcriptional responses of murine alveolar macrophages to elongated mineral particles of asbestiform and non-asbestiform varieties

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