title: Combinatorial epigenetic regulation of non-coding RNAs has profound effects on oncogenic pathways in breast cancer subtypes.
abstract: Although systematic genomic studies have identified a broad spectrum of non-coding RNAs (ncRNAs) that are involved in breast cancer, our understanding of the epigenetic dysregulation of those ncRNAs remains limited. Here, we systematically analysed the epigenetic alterations of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in two breast cancer subtypes (luminal and basal). Widespread epigenetic alterations of miRNAs and lncRNAs were observed in both cancer subtypes. In contrast to protein-coding genes, the majority of epigenetically dysregulated ncRNAs were shared between subtypes, but a subset of transcriptomic and corresponding epigenetic changes occurred in a subtype-specific manner. In addition, our findings suggested that various types of epi-modifications might synergistically modulate ncRNA transcription. Our observations further highlighted the complementary dysregulation of epi-modifications, particularly of miRNA members within the same family, which produced the same directed alterations as a result of diverse epi-modifications. Functional enrichment analysis revealed that epigenetically dysregulated ncRNAs were significantly involved in several hallmarks of cancers. Finally, our analysis of epigenetic modification-mediated miRNA regulatory networks revealed that cancer progression was associated with specific miRNA-gene modules in two subtypes. This study enhances understanding of the aberrant epigenetic patterns of ncRNA expression and provides new insights into the functions of ncRNAs in breast cancer subtypes.
authors.forename: Juan
authors.initials: J
authors.lastname: Xu
authors.forename: ZiShan
authors.initials: Z
authors.lastname: Wang
authors.forename: Shengli
authors.initials: S
authors.lastname: Li
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Jinwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Chunjie
authors.initials: C
authors.lastname: Jiang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Li
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D022661:RNA, Untranslated / Q000235:genetics*; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D035683:MicroRNAs; D022661:RNA, Untranslated
keywords: breast cancer subtypes; epigenetics; miRNA modules; non-coding RNAs; oncogentic pathways