Oncotarget

Research Papers:

A role for BRG1 in the regulation of genes required for development of the lymphatic system

Ajeet Pratap Singh _, Julie Foley, Arpit Tandon, Dhiral Phadke, H. Karimi Kinyamu and Trevor K. Archer

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Oncotarget. 2017; 8:54925-54938. https://doi.org/10.18632/oncotarget.18976

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Abstract

Ajeet Pratap Singh1,4, Julie Foley2, Arpit Tandon3, Dhiral Phadke3, H. Karimi Kinyamu1 and Trevor K. Archer1

1Chromatin and Gene Expression Section, Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

2Special Techniques Group, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

3Sciome.com, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA

4Present address: Cornell University, College of Veterinary Medicine, Ithaca, New York, USA

Correspondence to:

Ajeet Pratap Singh, email: [email protected]

Trevor K. Archer, email: [email protected]

Keywords: BRG1, LYVE1, development, lymphatic, lymphedema

Received: January 25, 2017     Accepted: June 16, 2017     Published: July 04, 2017

ABSTRACT

Lymphatic vasculature is an important part of the cardiovascular system with multiple functions, including regulation of the return of interstitial fluid (lymph) to the bloodstream, immune responses, and fat absorption. Consequently, lymphatic vasculature defects are involved in many pathological processes, including tumor metastasis and lymphedema. BRG1 is an important player in the developmental window when the lymphatic system is initiated. In the current study, we used tamoxifen inducible Rosa26CreERT2-BRG1floxed/floxed mice that allowed temporal analysis of the impact of BRG1 inactivation in the embryo. The BRG1floxed/floxed/Cre-TM embryos exhibited edema and hemorrhage at embryonic day-13 and began to die. BRG1 deficient embryos had abnormal lymphatic sac linings with fewer LYVE1 positive lymphatic endothelial cells. Indeed, loss of BRG1 attenuated expression of a subset of lymphatic genes in-vivo. Furthermore, BRG1 binds at the promoters of COUP-TFII and LYVE1, suggesting that BRG1 modulates expression of these genes in the developing embryos. Conversely, re-expression of BRG1 in cells lacking endogenous BRG1 resulted in induction of lymphatic gene expression in-vitro, suggesting that BRG1 was both required and sufficient for lymphatic gene expression. These studies provide important insights into intrinsic regulation of BRG1-mediated lymphatic-gene expression, and further an understanding of lymphatic gene dysregulation in lymphedema and other disease conditions.


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