Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling

Ivelisse Cajigas, David E. Leib, Jesse Cochrane, Hao Luo, Kelsey R. Swyter, Sean Chen, Brian S. Clark, James Thompson, John R. Yates, Robert E. Kingston, Jhumku D. Kohtz

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


Transcription-regulating long non-coding RNAs (lncRNAs) have the potential to control the site-specific expression of thousands of target genes. Previously, we showed that Evf2, the first described ultraconserved lncRNA, increases the association of transcriptional activators (DLX homeodomain proteins) with key DNA enhancers but represses gene expression. In this report, mass spectrometry shows that the Evf2-DLX1 ribonucleoprotein (RNP) contains the SWI/SNFrelated chromatin remodelers Brahma-related gene 1 (BRG1, SMARCA4) and Brahma-associated factor (BAF170, SMARCC2) in the developing mouse forebrain. Evf2 RNA colocalizes with BRG1 in nuclear clouds and increases BRG1 association with key DNA regulatory enhancers in the developing forebrain. While BRG1 directly interacts with DLX1 and Evf2 through distinct binding sites, Evf2 directly inhibits BRG1 ATPase and chromatin remodeling activities. In vitro studies show that both RNA-BRG1 binding and RNA inhibition of BRG1 ATPase/remodeling activity are promiscuous, suggesting that context is a crucial factor in RNAdependent chromatin remodeling inhibition. Together, these experiments support a model in which RNAs convert an active enhancer to a repressed enhancer by directly inhibiting chromatin remodeling activity, and address the apparent paradox of RNAmediated stabilization of transcriptional activators at enhancers with a repressive outcome. The importance of BRG1/RNA and BRG1/homeodomain interactions in neurodevelopmental disorders is underscored by the finding that mutations in Coffin–Siris syndrome, a human intellectual disability disorder, localize to the BRG1 RNAbinding and DLX1-binding domains.

Original languageEnglish
Pages (from-to)2641-2652
Number of pages12
JournalDevelopment (Cambridge)
Issue number15
StatePublished - Aug 1 2015


  • BRG1
  • Chromatin remodeling
  • Dlx6os1
  • Evf2
  • Homeodomain proteins
  • Long non-coding RNA


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