Singh Ajeet Pratap, Foley Julie, Tandon Arpit, Phadke Dhiral, Karimi Kinyamu H, Archer Trevor K
Chromatin 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.
Present address: Cornell University, College of Veterinary Medicine, Ithaca, New York, USA.
Oncotarget. 2017 Jul 4;8(33):54925-54938. doi: 10.18632/oncotarget.18976. eCollection 2017 Aug 15.
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 mice that allowed temporal analysis of the impact of BRG1 inactivation in the embryo. The 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 . Furthermore, BRG1 binds at the promoters of and , 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 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.
淋巴管系统是心血管系统的重要组成部分，具有多种功能，包括调节间质液（淋巴）回流至血液循环、免疫反应和脂肪吸收。因此，淋巴管系统缺陷参与了许多病理过程，包括肿瘤转移和淋巴水肿。BRG1是淋巴系统起始发育窗口期的一个重要因子。在本研究中，我们使用了他莫昔芬诱导型小鼠，以便对胚胎期BRG1失活的影响进行时间分析。胚胎在胚胎期第13天出现水肿和出血，并开始死亡。BRG1缺陷型胚胎的淋巴囊内衬异常，LYVE1阳性淋巴管内皮细胞减少。事实上，BRG1的缺失减弱了一部分淋巴基因的表达。此外，BRG1结合在 和 的启动子上，表明BRG1在发育中的胚胎中调节这些基因的表达。相反，在缺乏内源性BRG1的细胞中重新表达BRG1会导致淋巴基因表达的诱导，这表明BRG1对于淋巴基因表达既是必需的也是充分的。这些研究为BRG1介导的淋巴基因表达的内在调节提供了重要见解，并进一步加深了对淋巴水肿和其他疾病状态下淋巴基因失调的理解。
