Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma

• DOI: 10.1016/j.molcel.2022.03.018
• Publication Date: 2022-04-06T14:34:58Z
• Authors: Evgeny Deforzh; Erik J. Uhlmann; Eashita Das; Aleksandra Galitsyna; Ramil Arora; Harini Saravanan; Rosalia Rabinovsky; Aditya D. Wirawan; Nadiya M. Teplyuk; Rachid El Fatimy; Sucika Perumalla; Anirudh Jairam; Zhiyun Wei; Leonid Mirny; Anna M. Krichevsky
• Keywords: Gene Expression Regulation, Neoplastic; MicroRNAs; Cell Transformation, Neoplastic; Cell Line, Tumor; Humans; RNA, Long Noncoding; Glioma; Chromatin; Cell Proliferation

miR-10b is silenced in normal neuroglial cells of the brain but commonly activated in glioma, where it assumes an essential tumor-promoting role. We demonstrate that the entire miR-10b-hosting HOXD locus is activated in glioma via the cis-acting mechanism involving 3D chromatin reorganization and CTCF-cohesin-mediated looping. This mechanism requires two interacting lncRNAs, HOXD-AS2 and LINC01116, one associated with HOXD3/HOXD4/miR-10b promoter and another with the remote enhancer. Knockdown of either lncRNA in glioma cells alters CTCF and cohesin binding, abolishes chromatin looping, inhibits the expression of all genes within HOXD locus, and leads to glioma cell death. Conversely, in cortical astrocytes, enhancer activation is sufficient for HOXD/miR-10b locus reorganization, gene derepression, and neoplastic cell transformation. LINC01116 RNA is essential for this process. Our results demonstrate the interplay of two lncRNAs in the chromatin folding and concordant regulation of miR-10b and multiple HOXD genes normally silenced in astrocytes and triggering the neoplastic glial transformation.