Epigenomics-based identification of oestrogen-regulated long noncoding RNAs in ER+ breast cancer

Breast cancer is one of the most prevalent cancers in women worldwide. Through the regulation of many coding and non-coding target genes, oestrogen (E2 or 17β-oestradiol) and its nuclear receptor ERα play important roles in breast cancer development and progression. Despite the astounding advances in our understanding of oestrogen-regulated coding genes over the past decades, our knowledge on oestrogen-regulated non-coding targets has just begun to expand. Here we leverage epigenomic approaches to systematically analyse oestrogen-regulated long non-coding RNAs (lncRNAs). Similar to the coding targets of ERα, the transcription of oestrogen-regulated lncRNAs correlates with the activation status of ERα enhancers, measured by eRNA production, chromatin accessibility, and the occupancy of the enhancer regulatory components including P300, MED1, and ARID1B. Our 3D chromatin architecture analyses suggest that lncRNAs and their neighbouring E2-resonsive coding genes, exemplified by LINC00160 and RUNX1, might be regulated as a 3D structural unit resulted from enhancer-promoter interactions. Finally, we evaluated the expression levels of LINC00160 and RUNX1 in various types of breast cancer and found that their expression positively correlated with the survival rate in ER+ breast cancer patients, implying that the oestrogen-regulated LINC00160 and its neighbouring RUNX1 might represent potential biomarkers for ER+ breast cancers.

乳腺癌是全球女性最常见的恶性肿瘤之一。雌激素（E2或17β-雌二醇）及其核受体ERα通过调控众多编码和非编码目标基因，在乳腺癌的发生和发展过程中发挥着至关重要的作用。尽管过去几十年我们对雌激素调控的编码基因有了惊人的认识进展，但对于雌激素调控的非编码靶点的了解才刚刚起步。本研究利用表观遗传学方法，系统地分析了雌激素调控的长非编码RNA（lncRNA）。与ERα的编码靶标类似，雌激素调控的lncRNA的转录与ERα增强子的激活状态相关，这种激活状态可通过eRNA的产生、染色质可及性和增强子调控成分（包括P300、MED1和ARID1B）的富集来衡量。我们的三维染色质结构分析表明，lncRNA及其相邻的E2响应编码基因，如LINC00160和RUNX1，可能作为由增强子-启动子相互作用产生的一个三维结构单元受到调控。最后，我们评估了LINC00160和RUNX1在多种乳腺癌中的表达水平，并发现它们的表达与ER+乳腺癌患者的生存率呈正相关，这表明雌激素调控的LINC00160及其相邻的RUNX1可能代表ER+乳腺癌的潜在生物标志物。