Under various pathophysiological muscle-wasting conditions like diabetes and starvation, a family of ubiquitin ligases, including MuRF1 (Muscle specific RING-Finger protein 1), are induced to target muscle proteins for degradation via ubiquitination. In an attempt to identify the in vivo targets of MuRF1 we have generated transgenic mouse lines overexpressing MuRF1 in a skeletal muscle specific fashion. MuRF1-TG lines were viable and had normal fertility. Characterization of their skeletal muscles did not reveal evidence for muscle wasting at 10 weeks of age. In this experiment we compared the skeletal muscle transcriptome of transgenic mice with wildtypes.
MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies.
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We report the profiling of induced mRNA transcripts in two C. elegan replicate populations -- WT (N2) and mutant strain with deficient HLH30. Both strains were fed either OP50 strain of e-coli (normal feed) or S. aureus Overall design: Examination of infected versus uninfected wildtype and mutant lawns of animals
Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes.
Objectives: Systemic inflammation is a major risk factor for critical-illness myopathy (CIM) but its pathogenic role in muscle is uncertain. We observed that interleukin 6 (IL-6) and serum amyloid A1 (SAA1) expression was upregulated in muscle of critically ill patients. To test the relevance of these responses we assessed inflammation and acute-phase response at early and late time points in muscle of patients at risk for CIM.
Inflammation-induced acute phase response in skeletal muscle and critical illness myopathy.
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17-Estradiol (E2) is well known to be associated with uterine cancer, endometriosis, and leiomyomas. Although insulin-like growth factor I (IGF-I) has been identified as a mediator of the uterotrophic effect of E2 in several studies, this mechanism is still not well understood. In the present study, identification of the genes modulated by a physiological dose of E2, in the uterus, has been done in ovariectomized mice using Affymetrix microarrays. The E2-induced genomic profile shows that multiple genes belonging to the IGF-I pathway are affected after exposure to E2. Two phases of regulation could be identified. First, from 0 to 6 h, the expression of genes involved in the cell cycle, growth factors, protein tyrosine phosphatases, and MAPK phosphatases is quickly upregulated by E2, while IGF-I receptor and several genes of the MAPK and phosphatidylinositol 3-kinase pathways are downregulated. Later, i.e., from 6 to 24 h, transporters and peptidases/proteases are stimulated, whereas defense-related genes are differentially regulated by E2. Finally, cytoarchitectural genes are modulated later. The present data show that a physiological dose of E2 induces, within 24 h, a series of transcriptional events that promote the uterotrophic effect. Among these, the E2-mediated activation of the IGF-I pathway seems to play a pivotal role in the uterotrophic effect. Furthermore, the protein tyrosine phosphatases and MAPK phosphatases are likely to modulate the estrogenic uterotrophic action by targeting, at different steps, the IGF-I pathway.
Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus.
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Sequencing of RNA isolated from the tibialis anterior muscles of 6 month old C57BL/6J mice that had been injected and electroporated with either a control non-targeting siRNA (NT) or two different UBR4 targeting siRNA sequences (UBR4 siRNA5 and siRNA7) to deplete UBR4. Muscles were harvested 7 days after electroporation and showed significant loss of UBR4 coincident with hypertrophy of type 2A and 2X myofibers. Overall design: 3 samples each of non targeting control and 2 siRNA UBR4 targeting constructs.
A Key Role for the Ubiquitin Ligase UBR4 in Myofiber Hypertrophy in Drosophila and Mice.
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The response of bacteria to the conditions at the site of infection is a key part of the transcriptional program that will determine the sucess of the infectious agent. To model the environment of the distal airway, we used bovine pulmonary surfactant (Survanta). P. aeruginosa transcript levels were measured in the presence or absence of Survanta in MOPS minimal medium to identify transcripts altered in response to surfactant. The most highly induced transcript in Survanta was PA5325, renamed sphA based on our findings that the gene was specifically induced by sphingosine derived from the sphingomyelin present in pulmonary surfactant. A divergently transcribed transcription factor, PA5324, was demonstrated to be critical for the sphingosine dependent induction of sphA and was therefore renamed SphR. Microarrays of the sphR mutant cells were compared to wild type to determine the likely SphR regulon.
Detection of host-derived sphingosine by Pseudomonas aeruginosa is important for survival in the murine lung.
Despite 20 years since its discovery, the gene responsible for Huntington’s Disease, HTT, has still not had its function or transcriptional profile completely characterized. In response to a recent report by Ruzo et al. of several novel splice forms of HTT in human embryonic stem cell lines, we have analyzed a set of mRNA sequencing datasets from post mortem human brain from Huntington’s disease, Parkinson’s disease, and neurologically normal control subjects to evaluate support for previously observed and to identify novel splice patterns. A custom analysis pipeline produced supporting evidence for some of the results reported by two previous studies of alternative isoforms as well as identifying previously unreported splice patterns. All of the alternative splice patterns were of relatively low abundance compared to the canonical splice form. Overall design: 29 Huntington''s Disease, 29 Parkinson''s Disease, and 50 Neurologically normal control samples from human post-mortem prefrontal cortex
Evidence of Extensive Alternative Splicing in Post Mortem Human Brain HTT Transcription by mRNA Sequencing.
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We analyzed gene expression in human peripheral blood mononuclear cells (PBMCs) from breast cancer patients, patients with benign breast abnormalities, healthy cancer-free individuals as well as patients with other types of cancer (gastrointestinal and brain cancers).
Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors.
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