文章：

乳腺上皮细胞中TAZ结合位点的全基因组特征分析

Genome-Wide Characterization of TAZ Binding Sites in Mammary Epithelial Cells

原文发布日期：25 September 2023

DOI: 10.3390/cancers15194713

类型: Article

开放获取: 是

英文摘要：

The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast cancer (BLBC) patients. The oncogenic activity of TAZ involves the regulation of diverse signal transduction pathways that direct processes such as cell proliferation, migration, and resistance to apoptosis, albeit through poorly characterized gene expression programs. Here, using a tet-inducible system in mammary epithelial MCF10A cells, we have characterized the TAZ-regulated transcription program using RNA sequencing in a temporal and spatial manner. We further identified global TAZ binding sites at different TAZ activation time points by chromatin immunoprecipitation (ChIP) sequencing analysis. We found that the vast majority of TAZ was rapidly localized in enhancer regions at the early TAZ activation time point and then gradually spread to promoter regions. TAZ bound to enhancer regions following a switch in potential TEAD and FOSL2 transcription factor motifs. Furthermore, the ATAC sequencing analysis indicated that TAZ activation led to chromatin structural alterations. Together, our results have revealed the landscape of genome-wide TAZ binding sites and may lead to improvements in the current understanding of how TAZ regulates the gene expression program that contributes to the development of breast cancer.

摘要翻译： 

具有PDZ结合基序的转录共激活因子（TAZ）是Hippo信号通路的关键效应分子。我们及其他研究团队先前报道，在基底样乳腺癌（BLBC）患者中，TAZ的高表达水平与生存率降低及复发时间缩短呈正相关。TAZ的致癌活性涉及调控多种信号转导通路，这些通路指导细胞增殖、迁移及抗凋亡等过程，但其基因表达调控机制尚不明确。本研究利用乳腺上皮MCF10A细胞中的四环素诱导系统，通过RNA测序技术从时间和空间维度系统解析了TAZ调控的转录程序。进一步通过染色质免疫沉淀测序分析，我们在不同TAZ激活时间点鉴定了全基因组范围内的TAZ结合位点。研究发现，在TAZ激活早期，绝大多数TAZ迅速定位于增强子区域，随后逐渐扩散至启动子区域。TAZ在结合增强子区域时伴随着潜在TEAD和FOSL2转录因子基序的切换。此外，ATAC测序分析表明TAZ激活会导致染色质结构改变。综上，本研究揭示了TAZ在全基因组范围内的结合位点图谱，有望深化当前对TAZ如何通过调控基因表达程序促进乳腺癌发展的理解。

原文链接：

Genome-Wide Characterization of TAZ Binding Sites in Mammary Epithelial Cells