A major component of the cardiac stress response is the simultaneous activation of several gene regulatory networks. Interestingly, the transcriptional regulator steroid receptor coactivator-2, SRC-2 is often decreased during cardiac failure in humans. We postulated that SRC-2 suppression plays a mechanistic role in the stress response and that SRC-2 activity is an important regulator of the adult heart gene expression profile. Genome-wide microarray analysis, confirmed with targeted gene expression analyses revealed that genetic ablation of SRC-2 activates the fetal gene program in adult mice as manifested by shifts in expression of a) metabolic and b) sarcomeric genes, as well as associated modulating transcription factors. While these gene expression changes were not accompanied by changes in left ventricular weight or cardiac function, imposition of transverse aortic constriction (TAC) predisposed SRC-2 knockout (KO) mice to stress-induced cardiac dysfunction. In addition, SRC-2 KO mice lacked the normal ventricular hypertrophic response as indicated through heart weight, left ventricular wall thickness, and blunted molecular signaling known to activate hypertrophy. Our results indicate that SRC-2 is involved in maintenance of the steady-state adult heart transcriptional profile, with its ablation inducing transcriptional changes that mimic a stressed heart. These results further suggest that SRC-2 deletion interferes with the timing and integration needed to respond efficiently to stress through disruption of metabolic and sarcomeric gene expression and hypertrophic signaling, the three key stress responsive pathways.
SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart.
Sex, Specimen part
View SamplesOne of the most common genetic alterations in acute myeloid leukemia is the internal tandem duplication (ITD) in the FLT3 receptor for cytokine FLT3 ligand (FLT3L). The constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on normal hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. We report that young pre-leukemic mice with the Flt3ITD knock-in allele manifest an expansion of all DCs including classical (cDCs) and plasmacytoid (pDCs). The expansion originated in DC progenitors, occurred in a cell-intrinsic manner and was further enhanced in Flt3ITD/ITD mice. The mutation caused the downregulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Flt3ITD mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T cells (Tregs). Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity in the absence of Tregs. Thus, the FLT3-ITD mutation directly affects DC development, thereby indirectly modulating T cell homeostasis and supporting Treg expansion. This effect of FLT3-ITD may subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner. Overall design: Sorted splenic dendritic cell subsets from either Flt3+/+ or Flt3ITD/+ mice were sequenced for mRNA profiling. For each subset per genotype contains 2-3 replicates, all from independent experiments.
Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Promoter DNA methylation patterns of differentiated cells are largely programmed at the progenitor stage.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells.
Specimen part
View SamplesWe surveyed DNA methylation profiles of all human RefSeq promoters in relation to gene expression and differentiation in adipose tissue, bone marrow and muscle mesenchymal progenitors, as well as in bone marrow-derived hematopoietic progenitors. We unravel strongly overlapping DNA methylation profiles between adipose stem cells (ASCs), bone marrow mesenchymal stem cells (BMMSCs) and muscle progenitor cells (MPCs), while hematopoietic progenitor cells (HPCs) are more epigenetically distant from MSCs seen as a whole. Differentiation resolves a fraction of methylation patterns common to MSCs, generating epigenetic divergence.
Promoter DNA methylation patterns of differentiated cells are largely programmed at the progenitor stage.
Specimen part
View SamplesThe object of this study was to investigate the effect of elevated glucose concentrations (15 and 25 mM glucose) on gene expression in undifferentiated and adipogenic differentiated ASCs.
Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells.
Specimen part
View SamplesThe aim of this study was to characterize basal gene expression for proliferating adipose tissue MSCs, cultured at normal cell culture conditions.
Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells.
Specimen part
View SamplesCancer-related fatigue is one of the most frequent complaints among breast cancer survivors, with a major negative impact on general life. However, the etiology behind this syndrome is still unraveled. Gene expression analysis was performed on whole blood samples from breast cancer survivors classified as either fatigued or non-fatigued at two consecutive time points. The analysis identified several gene sets concerning plasma and B cell pathways as different between the fatigue and non-fatigue groups, suggesting that a deregulation in these pathways might underlie the fatigue syndrome. The fatigue group also showed a higher mean level of leucocytes, lymphocytes and neutrophiles compared with the non-fatigue group, thus further implicating the immune system in the biology behind the fatigue syndrome.
Alterations of gene expression in blood cells associated with chronic fatigue in breast cancer survivors.
Specimen part, Subject
View SamplesThe objective of the present study was to identify genes that are involved in increasing the ovulation number in mouse line FL1 that had been selected for high fertility performance.
Expression profiling of a high-fertility mouse line by microarray analysis and qPCR.
No sample metadata fields
View SamplesEpigenetic environment of histone H3.3 on promoters revealed by integration of imaging and genome-scale chromatin and methyl-DNA immunoprecipitation information.
Chromatin environment of histone variant H3.3 revealed by quantitative imaging and genome-scale chromatin and DNA immunoprecipitation.
Specimen part
View Samples