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Seo S.,Mayo Medical School | Seo S.,Chromatin | Lomberk G.,Chromatin | Mathison A.,Chromatin | And 7 more authors.
Journal of Biological Chemistry | Year: 2012

The importance of Krüppel-like factor (KLF)-mediated transcriptional pathways in the biochemistry of neuronal differentiation has been recognized relatively recently. Elegant studies have revealed that KLF proteins are important regulators of two major molecular and cellular processes critical for neuronal cell differentiation: neurite formation and the expression of neurotransmitter- related genes. However, whether KLF proteins mediate these key processes in a separate or coordinated fashion remains unknown. Moreover, knowledge on the contribution of chromatin dynamics to the biochemical mechanisms utilized by these proteins to perform their function is absent. Here we report the characterization of two antagonistic, chromatin-mediated mechanisms by which KLF11, also known as TIEG2 (transforming growth factor-β-inducible early gene 2) and MODYVII (maturity onset diabetes of the young VII), regulates transcription of the fopamine D2 receptor (Drd2) gene. First, KLF11 activates transcription by binding to a distinct Sp-KLF site within the Drd2 promoter (-98 to -94) and recruiting the p300 histone acetyltransferase. Second, Drd2 transcriptional activation is partially antagonized by heterochromatin protein 1 (HP1), the code reader for histone H3 lysine 9 methylation. Interestingly, KLF11 regulates neurotransmitter receptor gene expression in differentiating neuronal cell populations without affecting neurite formation. Overall, these studies highlight histone methylation and acetylation as key biochemical mechanisms modulating KLF-mediated neurotransmitter gene transcription. These data extend our knowledge of chromatin-mediated biochemical events that maintain key phenotypic features of differentiated neuronal cells. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Paris-Robidas S.,Laval University | Paris-Robidas S.,Center Hospitalier Of Luniversite Laval Research Center | Emond V.,Laval University | Emond V.,Center Hospitalier Of Luniversite Laval Research Center | And 6 more authors.
Molecular Pharmacology | Year: 2011

The development of vectors for drug delivery to the central nervous system remains a major pharmaceutical challenge. Here, we have characterized the brain distribution of two monoclonal antibodies (MAbs) targeting the mouse transferrin receptor (TfR) (clones Ri7 and 8D3) compared with control IgGs after intravenous injection into mice. MAbs were fluorolabeled with either Alexa Fluor (AF) dyes 647 or 750. Intravenous injection of Ri7 or 8D3 MAb coupled with AF750 led to higher fluorescence emission in brain homogenates compared with control IgGs, indicating retention in the brain. Fluorescence microscopy analysis revealed that AF647-Ri7 signal was confined to brain cerebrovasculature, colocalizing with an antibody against collagen IV, a marker of basal lamina. Confocal microscopy analysis confirmed the delivery of injected Ri7 MAb into brain endothelial cells using the pericyte marker anti-α-smooth muscle actin, the endothelial marker CD31, and the collagen IV antibody. No evidence of colocalization was detected with neurons or astrocytes identified using antibodies specific for neuronal nuclei or glial fibrillary acidic protein, respectively. Our data show that anti-TfR vectors injected intravenously readily accumulate into brain capillary endothelial cells, thus displaying strong drug-targeting potential. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics. Source

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