Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer with a very low survival rate and limited treatment options. Aberrant expression of MYC oncogene plays a crucial role in the progression of PDAC. Recent reports have established the significance of enhancer RNAs (eRNAs), originated from active enhancer or super-enhancer regions, in controlling gene transcription. Our study has identified how novel MYC eRNAs regulate MYC gene expression during chronic inflammatory condition in pancreatic cells. The higher amount of MYC eRNA has been observed in chronic pancreatitis and in pancreatic cancer patients as well. We have shown that MYC-490 kb eRNA interacts with YEATS2, a histone reader protein of ATAC-HAT complex and augments the association of YEATS2-containing ATAC complex to MYC promoter/enhancer region and thus increases MYC gene expression. A TNF-α induced Tyrosine dephosphorylation cycle regulates the MYC eRNA binding to YEATS2 protein in cancer cell. Thus, our study has added another layer of MYC gene expression regulation by enhancer-driven transcripts which can be used as a potential therapeutic target for treating pancreatic cancer. Nascent RNA sequencing of untreated and 24 hour TNFα treated cells. Please note that processed data generated from both replicates are linked to the corresponding rep1 records.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是最为常见且侵袭性极强的胰腺癌亚型，其生存率极低且治疗选择十分有限。MYC癌基因的异常表达在PDAC的疾病进展中发挥关键作用。近期研究已证实，源自活性增强子或超级增强子区域的增强子RNA（enhancer RNAs, eRNAs）在基因转录调控中具有重要意义。本研究阐明了新型MYC增强子RNA在胰腺细胞慢性炎症状态下对MYC基因表达的调控机制。慢性胰腺炎及胰腺癌患者体内均可检测到高水平的MYC增强子RNA。本研究证实，MYC-490 kb增强子RNA可与ATAC-HAT复合物的组蛋白阅读器蛋白YEATS2相结合，进而增强含YEATS2的ATAC复合物与MYC启动子/增强子区域的结合能力，最终上调MYC基因的表达水平。肿瘤细胞中，肿瘤坏死因子-α（TNF-α）诱导的酪氨酸脱磷酸循环可调控MYC增强子RNA与YEATS2蛋白的结合过程。综上，本研究揭示了增强子驱动转录本对MYC基因表达的另一层调控通路，该通路可作为胰腺癌治疗的潜在靶点。本数据集包含未经处理及经24小时TNF-α处理的细胞的新生RNA测序数据。请注意：两份生物学重复的处理后数据均关联至对应的rep1记录。