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Mus musculus
16 Downloadable Samples
Description
Adipose tissue plays an important role in storing excess nutrients and preventing ectopic lipid accumulation in other organs. Obesity leads to excess lipid storage in adipocytes, resulting in the generation of stress signals and the derangement of metabolic functions. SIRT1 is an important regulatory sensor of nutrient availability in many metabolic tissues. Here we report that SIRT1 functions in adipose tissue to protect from the development of inflammation and obesity under normal feeding conditions, and the progression to metabolic dysfunction under dietary stress. Genetic ablation of SIRT1 from adipose tissue leads to gene expression changes that highly overlap with changes induced by high fat diet in wild type mice, suggesting that dietary stress signals inhibit the activity of SIRT1. Indeed, we show that high fat diet induces the cleavage of SIRT1 in adipose tissue by the inflammation-activated caspase-1, providing a link between dietary stress and predisposition to metabolic dysfunction.
Publication Title
High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
Description
Homozygous mutation of the murine retinoblastoma tumor suppressor gene, Rb, results in embryonic lethality between E13.5 and E15.5 with defects in cellular proliferation, differentiation and apoptosis. Many of these defects are suppressed by mutation of an activating E2F, E2f1 or E2f3, indicating that they are key downstream targets of the retinoblastoma protein, pRB. In this study, we assess how E2F4 contributes to the developmental consequences of pRb-loss. In stark contrast to the activating E2Fs, the homozygous mutation of E2f4 shortened the lifespan of Rb-/- embryos. This resulted from an exacerbation of the placental defect of the Rb-/- mice indicating that E2F4 and pRB cooperate in the development of this tissue. Further analyses indicated that this defect reflects an increase in trophectoderm-like cells. Under conditions where the placenta was wild-type but the embryo mutant for E2f4 and pRb embryos survived to birth and exhibited all of the defects that were observed in the E2f4 and Rb single mutant embryos. Thus, while pRB and E2F4 cooperate in placental development, they play largely non-overlapping roles the development of many embryonic tissues.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 5 Downloadable Samples
Description
MicroRNAs (miRNAs) post-transcriptionally regulate the expression of thousands of distinct mRNAs. While some regulatory interactions help to maintain basal cellular functions, others are likely relevant in more specific settings, such as response to stress. Here we describe such a role for the mir-290-295 cluster, the dominant miRNA cluster in mouse embryonic stem cells (mESCs). Examination of a target list generated from bioinformatic prediction, as well as expression data following miRNA loss, revealed strong enrichment for apoptotic regulators, two of which we validated directly: Caspase 2, the most highly conserved mammalian caspase, and Ei24, a p53 transcriptional target. Consistent with these predictions, mESCs lacking miRNAs were more likely to initiate apoptosis following genotoxic exposure to gamma irradiation or doxorubicin. Knockdown of either candidate partially rescued this pro-apoptotic phenotype, as did transfection of members of the mir-290-295 cluster. These findings were recapitulated in a specific mir-290-295 deletion line, confirming that they reflect miRNA functions at physiological levels. In contrast to the basal regulatory roles previously identified, the pro-survival phenotype shown here may be most relevant to stressful gestations, where pro-oxidant metabolic states induce DNA damage. Similarly, this cluster may mediate chemotherapeutic resistance in a neoplastic context, making it a useful clinical target.
Publication Title
A latent pro-survival function for the mir-290-295 cluster in mouse embryonic stem cells.
Sample Metadata Fields
Specimen part
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GSE13765- Mus musculus
- 24 Downloadable Samples
Description
There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. While there are some well-characterized examples, the vast majority (>95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here, we report a new approach to identifying large non-coding RNAs (ncRNAs) by using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified ~1600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening ncRNAs (lincRNAs) exhibit strong purifying selection in their genomic loci, exonic sequences, and promoter regions with greater than 95% showing clear evolutionary conservation. We also developed a novel functional genomics approach that assigns putative functions to each lincRNA, revealing a diverse range of roles for lincRNAs in processes from ES pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFKB, Sox2, Oc4, and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 32 Downloadable Samples
Description
Expression profiles generated during dissection of the molecular mechanisms underlying direct reprogramming of somatic cells to a pluripotent state (induced pluripotent stem cells, iPS).
Publication Title
Dissecting direct reprogramming through integrative genomic analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 20 Downloadable Samples
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The impact of microRNAs on protein output.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Description
Exercise activates serine/threonine kinase AMPK and transcriptional factor PPARdelta that re-model metabolism and endurance capacity of skeletal muscle. Whether and how synthetic activation of these molecules regulated muscle gene signature is unknown.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
Mammalian genomes contain numerous DNA elements with potential transcription regulatory function but unknown target genes. We used transgenic, gain-of-function mice with an ectopic copy of the beta-globin locus control region (LCR) to better understand how regulatory elements dynamically search the genome for target genes. We find that the LCR samples a restricted nuclear sub-volume in which it forms preferential contacts with genes controlled by shared transcription factors. One contacted gene, betah1, located on another chromosome, is upregulated, providing genetic demonstration that mammalian enhancers can function between chromosomes. Upregulation is not pan-cellular but confined to selected jackpot cells significantly enriched for inter-chromosomal LCR-betah1 interactions. This implies that long-range DNA contacts are relatively stable and cell-specific and, when functional, cause variegated expression. We refer to this as spatial effect variegation (SEV). The data provide a dynamic and mechanistic framework for enhancer action, important for assigning function to the one- and three-dimensional structure of DNA.
Publication Title
Variegated gene expression caused by cell-specific long-range DNA interactions.
Sample Metadata Fields
Specimen part, Disease
View Samples- Mus musculus
- 8 Downloadable Samples
Description
This array analysis is to study developmental time course of the regulation of target messages expression during culture of murine neutrophils versus miR-223 null neutrophils. Culture media was SILAC-IMDM for MS analysis.
Publication Title
No associated publication
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Description
This array analysis is to study the regulation of target messages expression in in vitro cultured murine neutrophils versus miR-223 null neutrophils. Culture media was SILAC-IMDM for MS analysis.
Publication Title
The impact of microRNAs on protein output.
Sample Metadata Fields
No sample metadata fields
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