3D genome organization during TGFB-induced transcription requires nuclear microRNA and G-quadruplexes [RNA-Seq]

Chromatin is the physiological template for all biological processes in the eukaryotic cell nucleus. In addition, the structure of chromatin is intrinsically related to its function. Thus, studying the dynamics of three-dimensional (3D) chromatin structure is essential to understand these biological processes. Recent publications based on integrative analysis of multi-omics studies have provided comprehensive and multilevel insights into 3D genome organization emphasizing its role during transcriptional regulation. However, the function of nuclear microRNAs in 3D genome organization has remained elusive. Here we show that mature microRNA 9 (miR-9) is enriched at promoters and super-enhancers (SE) of genes that are inducible by tissue growth factor beta 1 (TGFB1) signaling. Further, we found that nuclear miR-9 is required for broad domains of the euchromatin histone mark H3K4me3 (histone 3 tri-methylated lysine 4), as well as the nucleic acid secondary structure G-quadruplexes (G4s), both are chromatin features related to increased transcriptional activity. Moreover, we show that nuclear miR-9 is required for promoter-super-enhancer looping. Our study places a nuclear microRNA in the same structural and functional context with G4s and promoter-enhancer interactions during 3D genome organization and transcriptional activation induced by TGFB1 signaling, a pathway that plays important role in hyperproliferative diseases, such as cancer and fibrosis.