Huntingtons Disease (HD) is an inherited neurodegenerative disease caused by a glutamine repeat expansion in huntingtin protein. Transcriptional deregulation and altered energy metabolism have been implicated in HD pathogenesis. We report here that mutant huntingtin causes disruption of mitochondrial function by inhibiting expression of PGC-1a, a transcriptional coactivator that regulates several metabolic processes including mitochondrial biogenesis and respiration. Mutant huntingtin represses PGC-1a gene transcription by associating with the promoter and interfering with the CREB/TAF4-dependent transcriptional pathway critical for the regulation of PGC-1a gene expression. Crossbreeding of PGC-1a knockout mice with HD knock-in mice leads to increased neurodegeneration of striatal neurons and motor abnormalities in the HD mice. Importantly, expression of PGC-1a partially reverses the toxic effects of mutant huntingtin in cultured striatal neurons. Moreover, lentiviral-mediated delivery of PGC-1a in the striatum provides neuroprotection in the transgenic HD mice. These studies suggest a key role for PGC-1a in the control of energy metabolism in the early stages of HD pathogenesis.
Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration.
Sex, Age, Specimen part
View SamplesAssociation of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in disease development. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in various cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA).
Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis.
Sex, Specimen part, Disease
View SamplesParkinsons Disease is a multi-system, disabling progressive neurodegenerative condition. Clinical progression is highly heterogeneous and, thus far, there are not available biomarkers to accurately predict the rate of disease progression. Thus, identifying molecular signatures that allow discriminating between different progression rates might significantly assist the therapeutic strategy, and enable improved outcomes in clinical trials.
Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles.
Sex, Specimen part
View SamplesPrimary colon CSC cultures were transduced with a Wnt responsive construct (TOP-GFP) and were single cell cloned. 10% highest and lowest TOP-GFP cell fractions were FACS sorted and arrayed.
Wnt activity defines colon cancer stem cells and is regulated by the microenvironment.
Specimen part
View SamplesThe study of the role of Drosophila Ada2b SAGA histone acetyltransferase component at early pupal stage (P4)
Genes of the ecdysone biosynthesis pathway are regulated by the dATAC histone acetyltransferase complex in Drosophila.
Sex, Age, Time
View SamplesT4 and T5 neurons are components of the neuronal circuit for motion vision in flies. To identify genes involved in neuronal computation of T4 and T5 neurons, we perfomed transcriptome analysis. Nuclei of T4 and T5 neurons were immunoprecipitated, total RNA was harvested and used for mRNA-seq with Illumina technology. In two biological replicates, we mapped 154 and 119 million reads to D. melanogaster genome. mRNA-seq provided information about expression levels of 17,468 annotated transcripts in the T4 and T5 neurons. Overall design: Cell type – specific transcriptome analysis of the RNA isolated from immunoprecipitated nuclei, performed in two biological replicates
RNA-Seq Transcriptome Analysis of Direction-Selective T4/T5 Neurons in Drosophila.
Subject
View SamplesRNA seq analyses were performed in granulosa cells (GCs) collected from gonadotropin treated ESR2 mutant rats. Data obtained from a null mutant with Esr2 exon 3 deletion (?3) and another DNA binding domain (DBD) mutant with exon 4 deletion (?4) were compared to that of wildtype (WT) rats. The raw data were analyzed using CLC genomics workbench. High quality RNA-sequencing reads were aligned to the Rattus norvegicus genome. Differentially expressed genes in ?3 or ?4 Esr2-mutant GCs were identified based on the following criteria: FDR p-Value =0.05 and an absolute fold change of 2. Fewer differentially expressed genes were identified in ?3 compared to the ?4 mutant group. As both of the mutant groups demonstrated a common phenotype of ovulation failure, differentially expressed genes common to both in ?3 and ?4 mutant rats were emphasized and further analyzed in the companion article “ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation” (Khristi et al., 2018).
ESR2 regulates granulosa cell genes essential for follicle maturation and ovulation.
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View SamplesThe Iroquois homeodomain transcription factor gene IRX3 is highly expressed in the developing nervous system, limb buds and heart. In adults, expression levels specify risk of obesity. We now report a significant functional role for IRX3 in human acute leukemia. While transcript levels are very low in normal human bone marrow cell populations, high level IRX3 expression is observed in ~30% of patients with acute myeloid leukemia (AML), ~50% of patients with T-acute lymphoblastic leukemia and ~20% of patients with B-acute lymphoblastic leukemia, typically in association with high levels of HOXA9. Expression of IRX3 alone was sufficient to immortalise murine bone marrow stem and progenitor cells, and induce T- and B-lineage leukemias in vivo with incomplete penetrance. IRX3 knockdown induced terminal differentiation of AML cells. Combined IRX3 and Hoxa9 expression in murine bone marrow stem and progenitor cells substantially enhanced the morphologic and phenotypic differentiation block of the resulting AMLs by comparison with Hoxa9-only leukemias, through suppression of a myelomonocytic program. Likewise, in cases of primary human AML, high IRX3 expression is associated with reduced myelomonocytic differentiation. Thus, tissue-inappropriate derepression of IRX3 modulates the cellular consequences of HOX gene expression to enhance differentiation block in human AML. Overall design: Murine acute myeloid leukemias - 3 samples from separate mice with AML initiated by HOXA9 and 3 samples from separate mice with AML initiated by HOXA9 and IRX3 coexpression
Derepression of the Iroquois Homeodomain Transcription Factor Gene IRX3 Confers Differentiation Block in Acute Leukemia.
Specimen part, Cell line, Subject
View SamplesThe activation of endothelium by tumor cells is one of the main steps by tumor metastasis. The role of the blood components (platelets and leukocytes) in this process remain unclear.
Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes.
Specimen part
View SamplesIt It is known that functional maturation of the small intestine occurring during the weaning period is facilitated by glucocorticoids (such as hydrocortisone, HC) including the increased expression of digestive hydrolases. However, the molecular mechanism(s) are not well understood, particularly in human gut. Here we report a microarray analysis of HC- induced changes in gene expression in H4 (a human fetal small intestinal epithelial cell line well-characterized in numerous previous studies). This study identified a large number of HC-affected genes, some involved in metabolism, cell cycle regulation, cell polarity, tight junction formation, and interactions with extracellular matrices. These effects could play an important role in HC-mediated enterocyte maturation in vivo and in vitro.
Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes.
Cell line, Treatment
View Samples