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Rattus norvegicus
6 Downloadable Samples
Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Math2 (NEX-1/NeuroD6) is a member of the bHLH transcription factor family and is involved in neuronal differentiation and maturation. In the present study, we identified the genes targeted by Math2 using DNA microarrays and cultured rat cortical cells transfected with Math2. Of the genes regulated by Math2, we focused on plasticity-related gene 1 (Prg1). Prg1 expression induced by Math2 was confirmed in cultured rat cortical cells and PC12 cells analyzed by real-time quantitative PCR. Examining the promoter region of rat Prg1, we found four E-boxes designated -E1 to -E4 (CANNTG) which were recognized by the bHLH transcription factor. Using chromatin immunoprecipitation (ChIP) assays, we found that Math2 directly bound to the E-box(es) in the Prg1 promoter. The reporter assay of Prg1 showed that -E1 was critical for the regulation of the Prg1 expression by Math2. Then, the functional role of Math2 and Prg1 was investigated in PC12 cells. Seventy-two hours after transfection of Math2 or Prg1, neurite length and number was significantly induced in PC12 cells. Co-transfection with Prg1-siRNA completely inhibited Math2-mediated morphological changes. Our results suggest that Math2 directly regulates Prg1 expression and Math2-Prg1 cascade plays an important role in neurite outgrowth in PC12 cells.
Publication Title
Prg1 is regulated by the basic helix-loop-helix transcription factor Math2.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The spectrum of genetic mutations differs among cancers in different organs, implying a cellular context-dependent effect of the genetic aberrations. However, the extent to which the cellular context affects the consequences of oncogenic mutations remains to be fully elucidated. We reprogrammed colon tumor cells in an Apc Min/+ mouse model, in which the loss of the Apc gene plays a critical role in tumor development, and established reprogrammed tumor cells (RTCs) that exhibit pluripotent stem cell (PSC)-like signatures of gene expression. We show that the majority of the genes in the RTCs that were affected by the Apc mutations did not overlap with the genes that were affected in the intestine or those that were affected by the accumulation of beta-catenin in PSCs. The RTCs lacked pluripotency but exhibited the increased expression of Cdx2 and a differentiation propensity that was biased toward the trophectoderm cell lineage. The genetic rescue of the mutated Apc allele conferred pluripotency on the RTCs and enabled their differentiation into various cell types in vivo. The re-disruption of Apc in the RTC-derived differentiated cells resulted in neoplastic growth that was exclusive to the intestine, yet the majority of intestinal lesions remained pre-tumoral microadenomas. These results highlight the significant influence of the cellular context on gene regulation, cellular plasticity, and cellular behavior in response to the loss of the Apc function. Our results also imply that transition from microadenomas to macroscopic tumors is reprogrammable, which underscores the importance of epigenetic regulation on colon tumor promotion.
Publication Title
Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior.
Sample Metadata Fields
Specimen part
View Samples- Schizosaccharomyces pombe
- 4 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The histone variant H2A.Z promotes initiation of meiotic recombination in fission yeast.
Sample Metadata Fields
No sample metadata fields
View Samples- Schizosaccharomyces pombe
- 4 Downloadable Samples
- Affymetrix Yeast Genome 2.0 Array (yeast2)
Description
Meiotic homologous recombination is a critical DNA-templated event for sexually-reproducing organisms. It is initiated by a programmed formation of DNA double strand breaks (DSBs), mainly formed at recombination hotspots, and is, like all other DNA-related processes, under great influence of chromatin structure. For example, local chromatin around hotspots directly impacts DSB formation. In addition, DSB is proposed to occur in a higher-order chromatin architecture termed axis-loop, in which many loops protrude from proteinaceous axis. Despite many recent insightful studies, still much remains unknown about how meiotic DSBs are generated in chromatin structure. Here, we show that the highly conserved histone H2A variant H2A.Z promotes meiotic DSB formation in fission yeast. Subsequent investigation revealed that H2A.Z is neither enriched around hotspots nor axis sites, and that transcript levels of DSB-promoting factors were maintained in the absence of H2A.Z. Instead, we found that H2A.Z facilitates chromatin binding of various proteins required for DSB formation. Strikingly, artificial tethering of one of such proteins, Rec10, to chromatin partially restored DSB reduction in H2A.Z-lacking cells. Based on these, we conclude that fission yeast H2A.Z promotes initiation of meiotic recombination partly through delivering DSB-related proteins onto chromatin.
Publication Title
The histone variant H2A.Z promotes initiation of meiotic recombination in fission yeast.
Sample Metadata Fields
No sample metadata fields
View Samples
GSE90034- Mus musculus
- 2 Downloadable Samples
Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Probe Name version), Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Multicellular organisms consist of multiple cell types, whose identities are maintained appropriately at locations where they are reside. The identity of each cell type is primarily maintained by cell-type-specific gene expression programs, but mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease -actin monomer resulted in nuclear accumulation of Mkl1 and the activation of Srf, which downregulated cell-type-specific genes and altered epigenetics in enhancers and chromatin organization. Mice overexpressing Srf exhibited various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.
Publication Title
Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
In vivo reprogramming drives Kras-induced cancer development.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Accumulation of genetic mutations is thought to be a primary cause of cancer. However, a set of genetic mutations sufficient for cancer development remains unclear in most cancers, including pancreatic cancer. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We first demonstrate that Kras and p53 mutations are insufficient to induce activation of ERK signaling and cancer development in the pancreas. We next show that short transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in repression of acinar cell enhancers and reversible loss of acinar cell properties. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma (PDAC). In contrast, forced expression of acinar cell-related transcription factors inhibits pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells.
Publication Title
In vivo reprogramming drives Kras-induced cancer development.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Oct3/4, Sox2, Klf4, and c-Myc re-wire somatic cells to achieve induced pluripotency (iPS cells). However, subtle differences in reprogramming methodology may confound comparative studies of reprogramming-induced gene expression changes. We specifically focused on the design of polycistronic reprogramming constructs, which encode all four factors linked with 2A peptides. Notably, publically available cassettes were found to employ one of two Klf4 variants (Klf4S and Klf4L; GenBank Accession Nos: AAC52939.1 and AAC04892.1), differing only by nine N-terminal amino acids. In a polycistronic context, these two variants generated dissimilar protein stoichiometry, where Klf4L vectors produced more Klf4 protein than those encoding Klf4S.
Publication Title
KLF4 N-terminal variance modulates induced reprogramming to pluripotency.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
There is a gradient of -catenin expression along the colonic crypt axis with the highest levels at the crypt bottom. However, it remains unclear whether different levels of canonical Wnt signaling exert distinct roles in the colonic epithelium. In the present study, we first showed that the canonical Wnt signaling is active in the proliferative compartment of normal colonic crypts by separating actively proliferating progenitor cells from non-proliferating cells in the colon using transgenic mice expressing a histone H2B-green fluorescent protein (GFP) fusion protein under the control of a tetracycline responsive regulatory element. Subsequently, we investigated the dose-dependent effect of canonical Wnt activation on colonic epithelial differentiation by controlling the expression levels of stabilized -catenin using a doxycycline-inducible transgenic system in mice. We show that elevated levels of Wnt signaling induce the amplification of Lgr5+ cells, which is accompanied by crypt fission and a reduction in cell proliferation among progenitor cells. In contrast, lower levels of -catenin induction enhanced cell proliferation rates of epithelial progenitors without affecting crypt fission rates. Notably, slow-cycling cells produced by -catenin activation exhibit activation of Notch signaling and the treatment of -catenin expressing mice with a Notch inhibitor turned such slow-cycling cells into actively proliferating cells. Our results indicate that the activation of the canonical Wnt signaling pathway is sufficient for de novo crypt formation, and suggest that different levels of canonical Wnt activations, in cooperation with Notch signaling, establish a hierarchy of slower-cycling stem cells and faster-cycling progenitor cells characteristic for the colonic epithelium.
Publication Title
Dose-dependent roles for canonical Wnt signalling in de novo crypt formation and cell cycle properties of the colonic epithelium.
Sample Metadata Fields
Sex, Specimen part
View Samples