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Nohara K.,Northwestern University | Liu S.,Northwestern University | Liu S.,Xiamen University | Meyers M.S.,Northwestern University | And 7 more authors.
Journal of Endocrinology | Year: 2013

Polycystic ovary syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. In this study, we determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropin concentrations. Hypothalamic KiSS1 neurons are believed to be critical to the onset of puberty and are the target of leptin. Adult NTM exhibited lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity, and decreased energy expenditure. They displayed a delayed increase in subcutaneous white adipose tissue amounts. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice. © 2013 Society for Endocrinology. Source


Ferron M.,Columbia University | Ferron M.,Institute Of Recherches Cliniques Of Montre Al | Settembre C.,Telethon Institute of Genetics and Medicine | Settembre C.,University of Naples Federico II | And 11 more authors.
Genes and Development | Year: 2013

Bone resorption by osteoclasts requires a large number of lysosomes that release proteases in the resorption lacuna. Whether lysosomal biogenesis is a consequence of the action of transcriptional regulators of osteoclast differentiation or is under the control of a different and specific transcriptional pathway remains unknown. We show here, through cell-based assays and cell-specific gene deletion experiments inmice, that the osteoclast differentiation factor RANKL promotes lysosomal biogenesis once osteoclasts are differentiated through the selective activation of TFEB, amember of the MITF/TFE family of transcription factors. This occurs following PKCβ phosphorylation of TFEB on three serine residues located in its last 15 amino acids. This post-translational modification stabilizes and increases the activity of this transcription factor. Supporting these biochemical observations, mice lacking in osteoclasts-either TFEB or PKCβ-show decreased lysosomal gene expression and increased bone mass. Altogether, these results uncover a RANKL-dependent signaling pathway taking place in differentiated osteoclasts and culminating in the activation of TFEB to enhance lysosomal biogenesis-a necessary step for proper bone resorption. © 2013 by Cold Spring Harbor Laboratory Press. Source


Smirnov P.,A+ Network | Safikhani Z.,A+ Network | Safikhani Z.,University of Toronto | El-Hachem N.,Institute Of Recherches Cliniques Of Montre Al | And 20 more authors.
Bioinformatics | Year: 2016

Pharmacogenomics holds great promise for the development of biomarkers of drug response and the design of new therapeutic options, which are key challenges in precision medicine. However, such data are scattered and lack standards for efficient access and analysis, consequently preventing the realization of the full potential of pharmacogenomics. To address these issues, we implemented PharmacoGx, an easy-to-use, open source package for integrative analysis of multiple pharmacogenomic datasets. We demonstrate the utility of our package in comparing large drug sensitivity datasets, such as the Genomics of Drug Sensitivity in Cancer and the Cancer Cell Line Encyclopedia. Moreover, we show how to use our package to easily perform Connectivity Map analysis. With increasing availability of drug-related data, our package will open new avenues of research for meta-analysis of pharmacogenomic data. © 2015 The Author. All rights reserved. Source


Khandanpour C.,Institute Of Recherches Cliniques Of Montre Al | Khandanpour C.,Universitatsklinikum Essen | Krongold J.,Institute Of Recherches Cliniques Of Montre Al | Schutte J.,University of Cambridge | And 19 more authors.
Blood | Year: 2012

The coding single nucleotide polymorphism GFI136N in the human gene growth factor independence 1 (GFI1) is present in 3%-7% of whites and increases the risk for acute myeloid leukemia (AML) by 60%. We show here that GFI136N, in contrast to GFI136S, lacks the ability to bind to the Gfi1 target gene that encodes the leukemia-associated transcription factor Hoxa9 and fails to initiate histone modifications that regulate HoxA9 expression. Consistent with this, AML patients heterozygous for the GFI136N variant show increased HOXA9 expression compared with normal controls. Using ChipSeq, we demonstrate that GFI136N specific epigenetic changes are also present in other genes involved in the development of AML. Moreover, granulomonocytic progenitors, a bone marrow subset from which AML can arise in humans and mice, show a proliferative expansion in the presence of the GFI136N variant. In addition, granulomonocytic progenitors carrying the GFI136N variant allele have altered gene expression patterns and differ in their ability to grow after transplantation. Finally, GFI136N can accelerate a K-RAS driven fatal myeloproliferative disease in mice. Our data suggest that the presence of a GFI136N variant allele induces a preleukemic state in myeloid precursors by deregulating the expression of Hoxa9 and other AML-related genes. © 2012 by The American Society of Hematology. Source

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