The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain

Ivelisse Cajigas, Abhijit Chakraborty, Kelsey R Swyter, Hao Luo, Monique Bastidas, Maximilliano Nigro, Elizabeth R Morris, Sean Chen, Michael J W VanGompel, David Leib, Sara J Kohtz, Marco Martina, Sooky Koh, Ferhat Ay, Jhumku D Kohtz

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)956-972.e9
JournalMolecular Cell
Volume71
Issue number6
DOIs
StatePublished - Sep 20 2018

Fingerprint Dive into the research topics of 'The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain'. Together they form a unique fingerprint.

  • Cite this

    Cajigas, I., Chakraborty, A., Swyter, K. R., Luo, H., Bastidas, M., Nigro, M., Morris, E. R., Chen, S., VanGompel, M. J. W., Leib, D., Kohtz, S. J., Martina, M., Koh, S., Ay, F., & Kohtz, J. D. (2018). The Evf2 Ultraconserved Enhancer lncRNA Functionally and Spatially Organizes Megabase Distant Genes in the Developing Forebrain. Molecular Cell, 71(6), 956-972.e9. https://doi.org/10.1016/j.molcel.2018.07.024