Normal arteries contain a large population of tissue resident macrophages (M). Their origins, as well as the mechanisms that sustain them during homeostasis and disease, however, are poorly understood. Gene expression profiling, we show, identifies arterial M as a distinct population among tissue M. Ontologically, arterial M arise before birth, though CX3CR1-, Csf1r-, and Flt3-driven fate mapping approaches demonstrate M colonization occurs through successive contributions of yolk sac (YS) and conventional hematopoiesis. In adulthood, arterial M renewal is driven by local proliferation rather than monocyte recruitment from the blood. Proliferation sustains M not only during steady state conditions, but mediates their rebound after severe depletion following sepsis. Importantly, the return of arterial M to functional homeostasis after infection is rapid; repopulated M exhibit a transcriptional program similar to resting M and efficiently phagocytose bacteria. Collectively, our data provide a detailed framework for future studies of arterial M function in health and disease.
Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth.
Sex, Specimen part
View SamplesHuntington’s disease (HD) is a devastating neurological disorder that is caused by an expansion of the poly-Q tract in exon 1 of the Huntingtin gene (HTT). HTT is an evolutionarily conserved and ubiquitously expressed protein that has been linked to a variety of functions including transcriptional regulation, mitochondrial function, and vesicle transport. This large protein has numerous caspase and calpain cleavage sites and can be decorated with several post-translational modifications such as phosphorylations, acetylations, sumoylations, and palmitoylations. However, the exact function of HTT and the role played by its modifications in the cell is still not well understood. Scrutiny of HTT function has been focused on a single, full length, mRNA. In this study, we report the discovery of 5 novel HTT mRNA splice isoforms that are expressed in normal and HD-hESC lines as well as cortical neurons differentiated from hESCs. Interestingly, none of the novel isoforms generates a truncated protein. Instead, 4 of the 5 new isoforms specifically eliminate domains and modifications to generate smaller HTT proteins. The fifth novel isoform incorporates a previously unreported additional exon, dubbed 41b, which is hominid-specific and introduces a potential phosphorylation site in the protein. The discovery of this hominid-specific isoform may shed light on human-specific pathogenic mechanisms of HTT, which could not be investigated with current mouse models of the disease. Furthermore, it provides a new human-specific target for drug screening in Huntington’s disease. Overall design: We performed RNAseq of human embryonic stem cells in pluripotency conditions to check expression of multiple HTT isoforms.
Discovery of novel isoforms of huntingtin reveals a new hominid-specific exon.
No sample metadata fields
View SamplesHsa-miR-500a-5p (miR500a) activity has been associated with breast cancer survival.
miR-500a-5p regulates oxidative stress response genes in breast cancer and predicts cancer survival.
Specimen part, Cell line
View SamplesCirculating tumor cells (CTCs) play a fundamental role in cancer progression. However, in mice, limited blood volume and the rarity of CTCs in the bloodstream preclude longitudinal, in-depth studies of these cells using existing liquid biopsy techniques. Here, we present an optofluidic system that continuously collects fluorescently-labeled CTCs from a genetically-engineered mouse model for several hours per day over multiple days or weeks. The system is based on a microfluidic cell-sorting chip connected serially to an un-anesthetized mouse via an implanted arteriovenous shunt. Pneumatically-controlled microfluidic valves capture CTCs as they flow through the device and CTC-depleted blood is returned back to the mouse via the shunt. To demonstrate the utility of our system, we profile CTCs isolated longitudinally from animals over a four-day treatment with the BET inhibitor JQ1 using single-cell RNA-Seq (scRNA-Seq) and show that our approach eliminates potential biases driven by inter-mouse heterogeneity that can occur when CTCs are collected across different mice. The CTC isolation and sorting technology presented here provides a research tool to help reveal details of how CTCs change over time, allowing studies to credential changes in CTCs as biomarkers of drug response and facilitating future studies to understand the role of CTCs in metastasis. Overall design: Single-cell RNA-Sequencing of CTCs and primary tumors from a murine model of non-small cell-lung cancer
Optofluidic real-time cell sorter for longitudinal CTC studies in mouse models of cancer.
Specimen part, Subject, Time
View SamplesThe aim of this study is to analyze the transcriptome of epithelial (CD326+ enriched) and immune (CD45+ enriched) fraction in Celiac Disease and controls to find differentially expressed genes.
The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region.
Sex, Age, Specimen part, Disease
View SamplesComplete global brain ischemia (CGBI) and reperfusion occur following resuscitation from cardiac arrest. Different brain neurons are selectively vulnerable to CGBI: pyramidal neurons of hippocampal CA3 survive 10 min CGBI but those of CA1 die at 3 days following 10 min CGBI. CA3 neurons are expected to have more robust stress responses and repair responses than CA1 neurons.
Embryonic lethal abnormal vision proteins and adenine and uridine-rich element mRNAs after global cerebral ischemia and reperfusion in the rat.
Sex, Specimen part
View SamplesClassical embryological studies revealed that during mid-embryogenesis vertebrates show similar morphologies. This “phylotypic stage” has recently received support from transcriptome analyses, which have also detected similar stages in nematodes and arthropods. A conserved stage in these three phyla has led us to ask if all animals pass through a universal definitive stage as a consequence of ancestral constraints on animal development. Previous work has suggested that HOX genes may comprise such a ‘zootypic’ stage, however this hypothetical stage has hitherto resisted systematic analysis. We have examined the embryonic development of ten different animals each of a fundamentally different phylum, including a segmented worm, a flatworm, a roundworm, a water bear, a fruitfly, a sea urchin, a zebrafish, a sea anemone, a sponge, and a comb jelly. For each species, we collected the embryonic transcriptomes at ~100 different developmental stages and analyzed their gene expression profiles. We found dynamic gene expression across all of the species that is structured in a stage like manner. Strikingly, we found that animal embryology contains two dominant modules of zygotic expression in terms of their protein domain composition: one involving proliferation, and a second involving differentiation. The switch between these two modules involves induction of the zootype; which in addition to homeobox containing genes, also involves Wnt and Notch signaling as well as forkhead domain transcription factors. Our results provide a systematic characterization of animal universality and identify the points of embryological constraints and flexibility. Overall design: 139 single embryo samples.
The mid-developmental transition and the evolution of animal body plans.
Subject
View SamplesClassical embryological studies revealed that during mid-embryogenesis vertebrates show similar morphologies. This “phylotypic stage” has recently received support from transcriptome analyses, which have also detected similar stages in nematodes and arthropods. A conserved stage in these three phyla has led us to ask if all animals pass through a universal definitive stage as a consequence of ancestral constraints on animal development. Previous work has suggested that HOX genes may comprise such a ‘zootypic’ stage, however this hypothetical stage has hitherto resisted systematic analysis. We have examined the embryonic development of ten different animals each of a fundamentally different phylum, including a segmented worm, a flatworm, a roundworm, a water bear, a fruitfly, a sea urchin, a zebrafish, a sea anemone, a sponge, and a comb jelly. For each species, we collected the embryonic transcriptomes at ~100 different developmental stages and analyzed their gene expression profiles. We found dynamic gene expression across all of the species that is structured in a stage like manner. Strikingly, we found that animal embryology contains two dominant modules of zygotic expression in terms of their protein domain composition: one involving proliferation, and a second involving differentiation. The switch between these two modules involves induction of the zootype; which in addition to homeobox containing genes, also involves Wnt and Notch signaling as well as forkhead domain transcription factors. Our results provide a systematic characterization of animal universality and identify the points of embryological constraints and flexibility. Overall design: 106 single embryo samples
The mid-developmental transition and the evolution of animal body plans.
No sample metadata fields
View SamplesClassical embryological studies revealed that during mid-embryogenesis vertebrates show similar morphologies. This “phylotypic stage” has recently received support from transcriptome analyses, which have also detected similar stages in nematodes and arthropods. A conserved stage in these three phyla has led us to ask if all animals pass through a universal definitive stage as a consequence of ancestral constraints on animal development. Previous work has suggested that HOX genes may comprise such a ‘zootypic’ stage, however this hypothetical stage has hitherto resisted systematic analysis. We have examined the embryonic development of ten different animals each of a fundamentally different phylum, including a segmented worm, a flatworm, a roundworm, a water bear, a fruitfly, a sea urchin, a zebrafish, a sea anemone, a sponge, and a comb jelly. For each species, we collected the embryonic transcriptomes at ~100 different developmental stages and analyzed their gene expression profiles. We found dynamic gene expression across all of the species that is structured in a stage like manner. Strikingly, we found that animal embryology contains two dominant modules of zygotic expression in terms of their protein domain composition: one involving proliferation, and a second involving differentiation. The switch between these two modules involves induction of the zootype; which in addition to homeobox containing genes, also involves Wnt and Notch signaling as well as forkhead domain transcription factors. Our results provide a systematic characterization of animal universality and identify the points of embryological constraints and flexibility. Overall design: 91 single embryo samples.
The mid-developmental transition and the evolution of animal body plans.
Subject
View SamplesWe treated logarithmically growing cultures of E.coli with a sub-lethal dose of an antimicrobial arylamide compound (PMX 10070) and Polymyxin B sulfate to measure transcriptional responses in an effort to understand mechanism of action
Antibacterial mechanism of action of arylamide foldamers.
No sample metadata fields
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