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Toronto, Canada

MacK S.C.,Hubrecht Institute for Developmental Biology and Stem Cell Research | MacK S.C.,University of Toronto | MacK S.C.,101 College St | Witt H.,German Cancer Research Center | And 17 more authors.
Brain Pathology

Ependymoma is the third most common pediatric brain tumor, yet because of the paucity of effective therapeutic interventions, 45% of patients remain incurable. Recent transcriptional and copy number profiling of the disease has identified few driver genes and in fact points to a balanced genomic profile. Candidate gene approaches looking at hypermethylated promoters and genome-wide epigenetic arrays suggest that DNA methylation may be critical to ependymoma pathogenesis. This review attempts to highlight existing and emerging evidence implicating the ependymoma epigenome as a key player and that epigenetic modifiers may offer new targeted therapeutic avenues for patients. © 2013 International Society of Neuropathology. Source

Milstone D.S.,Vascular Research Division | Ilyama M.,Toronto General Research Institute | Ilyama M.,University of Toronto | Ilyama M.,Kyoto University | And 22 more authors.
Circulation Research

Rationale: Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown. Objective: Determine the role of the 5′ NF-κB-binding element in expression of the endogenous Vcam1 gene. Methods and Results: Homologous recombination in embryonic stem cells was used to inactivate the 5′ NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5′ untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions. Conclusions: This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries. © 2015 American Heart Association, Inc. Source

Xu K.,101 College St | Nieuwenhuis E.,101 College St | Cohen B.L.,101 College St | Wang W.,101 College St | And 19 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology

Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells, and capillaries. Lunatic Fringe (Lfng) is a β 1-3 N-acetylglucosamine transferase that modifies Notch receptors to facilitate their activation by Delta-like (Dll1/4) ligands. Lfng is expressed in the distal lung during saccular development, and deletion of this gene impairs myofibroblast differentiation and alveogenesis in this context. A similar defect was observed in Notch2 β-geo/+Notch3 β-geo/β-geo compound mutant mice but not in Notch2 β-geo/+or Notch3 β-geo/β-geo single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo, we used ROSA26-rtTA /+;tetO-CRE /+;RBPJκ flox/flox inducible mutant mice to show that disruption of canonical Notch signaling during late embryonic development prevents induction of smooth muscle actin in mesenchymal cells of the distal lung. In sum, these results demonstrate that Lfng functions to enhance Notch signaling in myofibroblast precursor cells and thereby to coordinate differentiation and mobilization of myofibroblasts required for alveolar septation. Copyright © 2010 the American Physiological Society. Source

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