Zhu Wenyong, Huang Hao, Li Qiong, Gu Yu, Zhang Rongxin, Shu Huiling, Zhao Yunqi, Liu Hongde, Sun Xiao
State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing 211189, China.
Biomolecules. 2025 Apr 27;15(5):627. doi: 10.3390/biom15050627.
Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate for the lack of a systematic interpretation of the functional characterization and regulatory mechanisms of TCNE spatiotemporal activities, we developed a flexible pipeline, called captureTCNE, to depict the landscape of TCNEs and applied it to our breast cancer cohort (SEU-BRCA). Meanwhile, we investigated the genome-wide characteristics of TCNEs and unraveled that TCNEs harbor enhancer-like chromatin signatures as well as participate in the transcriptional machinery to regulate essential genes or architect biological regulatory networks of breast cancer. Specifically, the TCNE transcripts could recruit RBPs, such as ENOX1 and PTBP1, which are involved in gene expression regulation, to participate in the formation of regulatory networks and the association with altered splicing patterns. In particular, the presence of a non-classical secondary structure, called RNA G-quadruplex, on TCNE transcripts contributed to the recruitment of RBPs associated with subtype-specific transcriptional processes related to the estrogen response in breast cancer. Ultimately, we also analyzed the mutational signatures of variant-containing TCNEs and discerned twenty-one genes as essential components of the regulatory mechanism of TCNEs in breast cancer. Our study provides an effective TCNE identification pipeline and insights into the regulatory mechanisms of TCNEs in breast cancer, contributing to further knowledge of TCNEs and the emergence of innovative therapeutic strategies for breast cancer.
转录保守非编码元件（TCNEs）是可调节重要基因表达的非编码基因组元件，在主要与致癌作用相关的严重疾病发展中发挥的作用尚不清楚。目前，尚无用于鉴定TCNEs的成熟工具。为了弥补对TCNE时空活性的功能特征和调控机制缺乏系统解释的不足，我们开发了一种灵活的流程，称为captureTCNE，以描绘TCNEs的全貌，并将其应用于我们的乳腺癌队列（SEU-BRCA）。同时，我们研究了TCNEs的全基因组特征，发现TCNEs具有增强子样染色质特征，并参与转录机制以调节关键基因或构建乳腺癌的生物调控网络。具体而言，TCNE转录本可招募参与基因表达调控的RBP，如ENOX1和PTBP1，以参与调控网络的形成以及与可变剪接模式的关联。特别是，TCNE转录本上存在一种称为RNA G-四链体的非经典二级结构，有助于招募与乳腺癌雌激素反应相关的亚型特异性转录过程的RBP。最终，我们还分析了含变异TCNEs的突变特征，并识别出21个基因是乳腺癌中TCNEs调控机制的重要组成部分。我们的研究提供了一种有效的TCNE鉴定流程，并深入了解了TCNEs在乳腺癌中的调控机制，有助于进一步了解TCNEs以及乳腺癌创新治疗策略的出现。
