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GSE41799
Homo sapiens
16 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
Defining the aging-cancer relationship is a challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate many features of aging. However, their short lifespan and cell-intrinsic and -extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. To circumvent these limitations we have generated Zmpste24 mosaic mice. Interestingly, these mice develop normally - revealing cell-extrinsic mechanisms are preeminent in progeria- and display decreased incidence of infiltrating oral carcinomas. Moreover, ZMPSTE24 knock-down reduces human cancer cell invasiveness. Our results disclose the ZMPSTE24-prelamin A system as an example of antagonistic pleiotropy on cancer and aging, support the potential of cell-based and systemic therapies for progeria, and highlight ZMPSTE24 as a new anticancer target.
Publication Title
Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. We report herein a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. By using this animal model, we have developed an antisense morpholinobased therapy that prevents the pathogenic Lmna splicing, dramatically reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotidebased therapies for treating human diseases of accelerated aging.
Publication Title
Splicing-directed therapy in a new mouse model of human accelerated aging.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina MouseWG-6 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Primary cell cultures were isolated from KrasG12D-driven, PiggyBac transposon-transposase pancreatic cancer cell cultures and subjected to microarray-based expression profiling for the investigation of expression profiles.
Publication Title
Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 3 Downloadable Samples
Illumina HiSeq 2000
Description
Self-renewal and pluripotency in human embryonic stem cells (hESCs) depends upon the function of a remarkably small number of master transcription factors (TFs) that include OCT4, SOX2, and NANOG. Endogenous factors that regulate and maintain the expression of master TFs in hESCs remain largely unknown and/or uncharacterized. We use a genome-wide, proteomics approach to identify proteins associated with the OCT4 enhancer. We identify known OCT4 regulators, plus a subset of potential regulators including a zinc finger protein, ZNF207, that plays diverse roles during development. In hESCs, ZNF207 partners with master pluripotency TFs to govern self-renewal and pluripotency while simultaneously controlling commitment of cells towards ectoderm through direct regulation of neuronal TFs, including OTX2. The distinct roles of ZNF207 during differentiation occur via isoform switching. Thus, a distinct isoform of ZNF207 functions in hESCs at the nexus that balances pluripotency and differentiation to ectoderm. Overall design: examine gene expression changes in ZNF207 knock down hESCs
Publication Title
A distinct isoform of ZNF207 controls self-renewal and pluripotency of human embryonic stem cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 204 Downloadable Samples
- Illumina HiSeq 2000
Description
Cortical GABAergic interneurons constitute a highly diverse population of inhibitory neurons that are key regulators of cortical microcircuit function. An important and heterogeneous group of cortical interneurons specifically expresses the serotonin receptor 3A (5-HT3AR) but how this diversity emerges during development is poorly understood. Here we use single-cell transcriptomics to identify gene expression patterns operating in Htr3a-GFP+ interneurons during early steps of cortical circuit assembly. We identify 3 main molecular types of Htr3a-GFP+ interneurons, each displaying distinct developmental dynamics of gene expression. The transcription factor Meis2 is specifically enriched in a type of Htr3a-GFP+ interneurons spatially confined to the cortical white matter. These MEIS2 expressing interneurons appear to originate from a restricted region located at the embryonic pallial-subpallial boundary. Overall, this study identifies MEIS2 as a subclass-specific marker for 5-HT3AR-containing interstitial interneurons and demonstrates that the transcriptional and anatomical parcellation of cortical interneurons is developmentally coupled. Overall design: Single cell transcriptomics of cortical interneurons FACS sorted according to GFP-Htr3a+. Acquired from mouse brains of 3 different developmental ages: E18, P2, P5
Publication Title
Transcriptomic and anatomic parcellation of 5-HT<sub>3A</sub>R expressing cortical interneuron subtypes revealed by single-cell RNA sequencing.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 2756 Downloadable Samples
- Illumina HiSeq 2500
Description
During cortical development, distinct subtypes of glutamatergic neurons are sequentially born and differentiate from dynamic populations of progenitors. How progenitors and their daughter cells are temporally patterned remains unknown. Here, we trace the transcriptional trajectories of successive generations of apical progenitors (APs) and isochronic cohorts of their daughter neurons in the developing mouse neocortex using high temporal resolution parallel single-cell RNA sequencing. We identify and functionally characterize a core set of evolutionarily-conserved temporally patterned genes which drive APs from internally-driven states to more exteroceptive states, revealing a progressively increasing role for extracellular signals as corticogenesis unfolds. These embryonic age-dependent AP molecular states are reflected in their neuronal progeny as successive ground states, onto which essentially conserved early post-mitotic differentiation programs are applied. Thus, temporally unfolding molecular birthmarks present in progenitors act in their post-mitotic progeny as seeds for adult neuronal diversity. Overall design: Investigation of the transcriptional dynamics in time-locked cohorts of cortical cells across embryonic neurogenesis. Flashtag is injected at 4 ages (E12, E13, E14, E15), and cells collected 1H, 24H, 96H after birth (= a total of 12 conditions) and analyzed by single cell transcriptomics.
Publication Title
Temporal patterning of apical progenitors and their daughter neurons in the developing neocortex.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
With this study we wanted to evaluate the impact of murine norovirus infection of germfree mice and to compare it to germfree mice which have received fecal transplants of conventional mice. Overall design: whole small intestinal tissue analysis of 3 germfree, 3 germfree mice infected with murine norovirus and 3 conventionalized germfree mice
Publication Title
An enteric virus can replace the beneficial function of commensal bacteria.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 23 Downloadable Samples
- Illumina HiSeq 2000, Ion Torrent Proton
Description
Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (~100–1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients. Overall design: To compare the RNA Seq profiles from the cortex and spinal cord of transgenic mice expressing unexpanded human C9orf72 (F08, n=4), expanded human C9orf72 (F112, n=3/4), and nontransgenic controls (n=4).
Publication Title
C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Nod2 has been extensively characterized as a bacterial sensor that induces an antimicrobial and inflammatory gene expression program. Therefore, it is unclear why Nod2 mutations that disrupt bacterial recognition are paradoxically among the highest risk factors for Crohns disease, which involves an exaggerated immune response directed at intestinal bacteria. Previous studies from our lab have shown that mice deficient in Atg16L1, another Crohns disease susceptibility gene, develop abnormalities in Paneth cells, specialized epithelial cells in the small intestine involved in antimicrobial responses.
Publication Title
Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus.
Sample Metadata Fields
Age, Specimen part
View Samples