关键词：乳腺癌；遗传学；组蛋白转录（遗传学）
摘 要：The overall objective of this work is to create novel chromatin engines , named Designed Epigenetic Remodeling Factors (DERFs). These factors will be designed to recognize 18-base pairs (bp) specific sequences in self- renewal gene promoters (found up-regulated in CSCs). These proteins will then incorporate specific silencing marks, which will trigger endogenous self- renewal gene silencing. Thus, the IDEA is to direct the chromatin editing of the breast cancer stem genome, by altering the collection of the epigenetic marks at specific histone tails ( histone code or histone grammar ) in CSCs. As a proof of principle, we will focus on the gene promoter SOX2, which plays a critical role controlling self-renewal of CSCs (10). Our specific hypothesis is that the delivery of sequence-specific ZF domains (engineered to bind the SOX2 promoter) tethered to specific silencing enzymes will result on forced epigenetic silencing of SOX2, inhibition of CSC self-renewal and inhibition of tumorigenicity in a mouse model of breast cancer.