Cited by 82Cancer-related molecular mechanisms researchGenomics and Chromatin DynamicsDevelopmental Biology and Gene Regulation

The Evf2 ultraconserved enhancer lncRNA functionally and spatially organizes megabase distant genes in the developing forebrain

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Cajigas, Ivelisse, Chakraborty, Abhijit, Swyter, Kelsey R., Luo, Hao, Bastidas, Monique, Nigro, Maximilliano, Morris, Elizabeth R., Chen, Sean +7 more·2018·Molecular Cell

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.

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Crossref · 10.1016/j.molcel.2018.07.024

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  • DLX5/6-N-Haplotype covers the complete sequence of DLX6, the DLX5/6 intergenic region, the second intron and third exon of DLX5, three known enhancers for brain expression of DLX5/6 (I56i, I56ii, and Mef2-BA), and the three first exons of the long noncoding RNA asDLX6nc.

    “The DLX5/6-N-Haplotype covers the complete sequence of DLX6, the DLX5/6 intergenic region, the second intron and third exon of DLX5, three known enhancers for brain expression of DLX5/6: I56i, I56ii, and Mef2-BA (Birnbaum, et al. 2012), and the three first exons of the long noncoding RNA asDLX6nc, which has been implicated in GABAergic neuronal differentiation (Cajigas, et al. 2018).”

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Authors
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.
Affiliations
  • Northwestern University (US)
  • La Jolla Institute for Immunology (US)
  • Emory University (US)
Corresponding author
Kohtz, Jhumku D.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2018-09
Volume
71
Issue
6
Pages
956-972.e9
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2888282391
Cited by
82
References
75
Citations by year
2026: 5 · 2025: 14 · 2024: 11 · 2023: 12 · 2022: 8 · 2021: 11 · 2020: 8 · 2019: 12 · 2018: 1
FWCI
2.41
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIMH (R01MH094653, R01MH111267)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
long non-coding RNA, GABAergic interneurons, forebrain development, chromosome topology, mevalonate pathway, interneuron diversity, seizure susceptibility, enhancer repression, enhancer activation
MeSH terms
Cohesins, Alcohol Oxidoreductases, Animals, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Interneurons, Transcription Factors, Prosencephalon, Conserved Sequence, Homeodomain Proteins, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Mice, Neurogenesis, RNA, Long Noncoding

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