Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung cancer, is a significant cause of cancer-related mortality due to late-stage diagnoses and limited treatment options. Identifying effective biomarkers is crucial for improving prognosis and therapeutic strategies. miR-30a-5p has emerged as a potential tumor suppressor in LUAD, yet its exact role remains unclear. In this study, we analyzed three miRNA expression datasets from the GEO database and confirmed miR-30a downregulation in LUAD through TCGA and qRT-PCR validation. We identified MYBL2, TWF1, GALNT7, and PFN2 as oncogenic targets of miR-30a by integrating miRNA target predictions with gene expression data. Expression and survival analyses revealed an inverse relationship between miR-30a and these targets, with high expression levels correlating with poor patient outcomes. Functional enrichment analysis highlighted pathways in cell cycle regulation and actin cytoskeleton organization. Our findings underscore the significance of the miR-30a regulatory network in LUAD progression, positioning miR-30a and its targets as promising prognostic biomarkers and therapeutic targets.

More than twenty years ago, the FANTOM consortium uncovered that mammalian genomes are pervasively transcribed, revealing multitudes of RNAs with unknown functions. A subset of these transcripts has since then been linked to transcriptional control and to chromatin organization via their ability to interact with DNA, suggesting that chromatin-associated RNAs could be key players in genome regulation. Although recent technological advances now enable the mapping of genome-wide RNA-DNA contacts, a lack of analyses integrating these methods with other genomic features and across multiple cellular contexts hinders our comprehensive understanding of the principles underlying RNA-DNA interactions and of their biological importance. As part of the FANTOM6 project, we thus generated RNA-DNA interaction maps in 16 different human cell types, then combined these contacts with multiple layers of other genomic data to investigate how patterns of interaction between RNA and DNA relate to chromatin organization and function. We show that the RNA-DNA interactome is highly dynamic yet reproducibly organized in cell-type specific networks, constituted of a great diversity of interactions that vary in function of their distance, the nature of their sources and the chromatin state of their targets. In particular, we detected numerous regulatory elements that exhibit marked changes in activity when differentially bound by transcripts, implying that thousands of RNA-DNA interactions can play a mechanistic role in gene expression. This regulatory function correlates with RNA-protein interactions and significantly associates with cell type-relevant and disorder-related traits. In addition to providing essential resources for future research in RNA-mediated chromatin regulation, cellular biology and human diseases, our study thus establishes the RNA-DNA interactome as a new genome regulatory layer that defines and maintains cellular identity and behavior.