Dissecting the Emerging Regulatory and Mechanistic Paradigms of Transcribed Conserved Non-Coding Elements in Breast Cancer

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.