Abstract
Gene regulation requires selective targeting of DNA regulatory enhancers over megabase distances. Here we show that Evf2, a cloud-forming Dlx5/6 ultraconserved enhancer (UCE) lncRNA, simultaneously localizes to activated (Umad1, 1.6 Mb distant) and repressed (Akr1b8, 27 Mb distant) chr6 target genes, precisely regulating UCE-gene distances and cohesin binding in mouse embryonic forebrain GABAergic interneurons (INs). Transgene expression of Evf2 activates Lsm8 (12 Mb distant) but fails to repress Akr1b8, supporting trans activation and long-range cis repression. Through both short-range (Dlx6 antisense) and long-range (Akr1b8) repression, the Evf2-5'UCE links homeodomain and mevalonate pathway-regulated enhancers to IN diversity. The Evf2-3' end is required for long-range activation but dispensable for RNA cloud localization, functionally dividing the RNA into 3'-activator and 5'UCE repressor and targeting regions. Together, these results support that Evf2 selectively regulates UCE interactions with multi-megabase distant genes through complex effects on chromosome topology, linking lncRNA-dependent topological and transcriptional control with interneuron diversity and seizure susceptibility.
Citations
Oct 5, 2019·International Journal of Molecular Sciences·Chiara VillaRomina Combi
Dec 5, 2019·Scientific Reports·Santhilal SubhashSouvik Kar
Jan 5, 2020·Cold Spring Harbor Symposia on Quantitative Biology·Hadas HezroniIgor Ulitsky
Jan 30, 2020·Frontiers in Cell and Developmental Biology·Preston R ArnoldXian C Li
Feb 8, 2019·Frontiers in Genetics·Ling LiXuekun Li
Apr 12, 2019·The Biochemical Journal·Emily J ShieldsRoberto Bonasio
Feb 20, 2020·Nature Communications·Elena GrossiMaite Huarte
Oct 15, 2019·Frontiers in Oncology·Xiaofeng DaiJianying Zhang
Oct 31, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Roopa Thapar
May 16, 2019·Nature Reviews. Genetics·Stefan Schoenfelder, Peter Fraser
Dec 13, 2019·BioMed Research International·Sanyang ChenShuijun Zhang
Apr 29, 2020·International Journal of Molecular Sciences·Katharina JonasMartin Pichler
Apr 17, 2020·Genes & Genomics·Youngtae Kwon, Yun Doo Chung
Sep 26, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Eva D'haene, Sarah Vergult
Dec 18, 2020·Anesthesia and Analgesia·Tarun PantZeljko J Bosnjak
Jan 13, 2021·Nature Communications·Nicholas T CrumpThomas A Milne
Feb 21, 2021·Metabolic Brain Disease·Parinita Mishra, Santosh Kumar
Mar 11, 2021·Developmental Cell·Granton A Jindal, Emma K Farley
Feb 18, 2021·Development·Ivelisse CajigasJhumku D Kohtz
Apr 4, 2021·Non-coding RNA·Isabela I BarrosWilson A Silva
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sarva KeihaniEugenio F Fornasiero
Jun 17, 2021·Molecular Biology and Evolution·Giovanni LeviNicolas Narboux-Nême
May 22, 2021·Cancer Research·Santanu AdhikaryChandrima Das