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Epigenetic and functional changes in differentiation and proliferation induced by BORIS expression

BORIS 表达诱导的分化和增殖的表观遗传和功能变化

基本信息

批准号：
210694066
负责人：
Professor Dr. Rainer Renkawitz
金额：
--
依托单位：
Institut für Genetik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/210694066?language=en
关键词：
Epigenetic functional changes differentiation proliferation

项目摘要

The major expression of the conserved transcription factor BORIS in mouse and man is restricted to germ line cells. This factor is paralogous to the essential and ubiquitous regulator CTCF, which is not expressed in testis. In contrast to this normal situation, BORIS expression has been identified in many tumor cell lines and in tumor tissues. Since CTCF and BORIS bind to identical or at least similar DNA sequences, a competition between these factors can be expected in pathological cases positive for BORIS expression. Published and own preliminary experiments show that both factors differ in their molecular function extremely, including BORIS mediated changes in DNA methylation. We would like to understand the consequences of pathological BORIS expression at the molecular level on all target sites in the genome. An important focus will be on the changes on DNA methylation, which plays an important role not only for gene activity, but also for the control of alternative promoters in the gene body. For this we will use the mouse ES cell system with the integrated gene for cre recombinase flanked by loxP elements to generate Tet regulated BORIS expression. BORIS mediated effects on DNA methylation during ES cell proliferation and differentiation will be tested on a genome-wide scale.

保守转录因子BORIS在小鼠和人中的主要表达限于生殖系细胞。该因子与在睾丸中不表达的必需且普遍存在的调节因子CTCF是旁系同源的。与这种正常情况相反，BORIS表达已在许多肿瘤细胞系和肿瘤组织中鉴定。由于CTCF和BORIS与相同或至少相似的DNA序列结合，因此在BORIS表达阳性的病理病例中，可以预期这些因子之间的竞争。已发表的和自己的初步实验表明，这两种因子在分子功能上存在极大差异，包括BORIS介导的DNA甲基化变化。我们希望了解病理BORIS表达在基因组中所有靶位点上的分子水平上的后果。一个重要的焦点将是DNA甲基化的变化，它不仅对基因活性起着重要作用，而且对基因体中替代启动子的控制也起着重要作用。为此，我们将使用具有整合的cre重组酶基因的小鼠ES细胞系统，其侧翼为loxP元件，以产生Tet调节的BORIS表达。将在全基因组范围内测试BORIS介导的ES细胞增殖和分化过程中对DNA甲基化的影响。