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Transcriptional Dysregulation (transcriptional + dysregulation)

Distribution by Scientific Domains
Life Sciences50%

Selected Abstracts

Tissue-specific dysregulation of DNA methylation in aging

AGING CELL, Issue 4 2010
Reid F. Thompson
Summary The normal aging process is a complex phenomenon associated with physiological alterations in the function of cells and organs over time. Although an attractive candidate for mediating transcriptional dysregulation, the contribution of epigenetic dysregulation to these progressive changes in cellular physiology remains unclear. In this study, we employed the genome-wide HpaII tiny fragment enrichment by ligation-mediated PCR assay to define patterns of cytosine methylation throughout the rat genome and the luminometric methylation analysis assay to measure global levels of DNA methylation in the same samples. We studied both liver and visceral adipose tissues and demonstrated significant differences in DNA methylation with age at > 5% of sites analyzed. Furthermore, we showed that epigenetic dysregulation with age is a highly tissue-dependent phenomenon. The most distinctive loci were located at intergenic sequences and conserved noncoding elements, and not at promoters nor at CG-dinucleotide-dense loci. Despite this, we found that there was a subset of genes at which cytosine methylation and gene expression changes were concordant. Finally, we demonstrated that changes in methylation occur consistently near genes that are involved in metabolism and metabolic regulation, implicating their potential role in the pathogenesis of age-related diseases. We conclude that different patterns of epigenetic dysregulation occur in each tissue over time and may cause some of the physiological changes associated with normal aging. [source]

Comprehensive proteomic and transcriptomic analysis reveals early induction of a protective anti-oxidative stress response by low-dose proteasome inhibition

PROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 12 2009
Sven Bieler
Abstract Effective inhibition of the proteasome by high doses of proteasome inhibitors induces apoptotic cell death. In contrast, partial proteasome inhibition by low inhibitor doses mediates a protective cellular stress response. The early targets and mediators of these dose-dependent effects of proteasome inhibitors are unknown. Primary human umbilical cord vein endothelial cells were treated with low and high doses of the proteasome inhibitor MG132 for 2,h. In a combined 2-DE and MS approach, we identified more than 20 new targets of proteasome inhibition. These proteins are involved in cell cycle regulation, signaling, cytoskeletal rearrangement, and cellular stress response. Accompanying Affymetrix analysis revealed that these proteins are not regulated on the transcriptional level but are mainly stabilized by proteasome inhibition. The proteasome-dependent accumulation of the anti-oxidative sensor proteins DJ-1, peroxiredoxin-1 and -6 was accompanied by dose-dependent induction of oxidative stress after 2,h of proteasome inhibition and contributed to the differential transcriptional stress response to low- and high-dose proteasome inhibition: Whereas low-dose proteasome inhibition induces a transcriptional profile reminiscent of a physiological stress response that preconditions and protects endothelial cells from oxidative stress, high inhibitor doses induce massive transcriptional dysregulation and pronounced oxidative stress triggering apoptosis. [source]

Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease

ANNALS OF NEUROLOGY, Issue 2 2010
Hitoshi Osaka MD
Mutations in the gap junction protein gamma-2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus-Merzbacher-like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.-167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10 -to- GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations. ANN NEUROL 2010;68:250,254 [source]

Spectrin mutations in spinocerebellar ataxia (SCA)

BIOESSAYS, Issue 8 2006
Peter Bauer
Recently, ,III spectrins have been recognized as ataxia disease genes, with the identification by Ikeda and co-workers of pathogenic mutations in the SPTBN2 gene in three large (and mapped) SCA5 families of American and European origin.(1) With their discovery, the large "Lincoln" family has been traced back to the underlying genetic defect for the slowly progressive cerebellar ataxia. In addition, the involvement of this component of the cytoskeleton directs attention towards the possible role of organelle stability during neurodegeneration. The findings suggest that the mechanical properties of neurons and their dynamics may be as important as altered Ca2+ homeostasis, transcriptional dysregulation, and impaired protein degradation in neurodegeneration conditions. BioEssays 28: 785,787, 2006. © 2006 Wiley Periodicals, Inc. [source]