RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity

Cell. 2015 May 7;161(4):774-89. doi: 10.1016/j.cell.2015.04.034.


We have ablated the cellular RNA degradation machinery in differentiated B cells and pluripotent embryonic stem cells (ESCs) by conditional mutagenesis of core (Exosc3) and nuclear RNase (Exosc10) components of RNA exosome and identified a vast number of long non-coding RNAs (lncRNAs) and enhancer RNAs (eRNAs) with emergent functionality. Unexpectedly, eRNA-expressing regions accumulate R-loop structures upon RNA exosome ablation, thus demonstrating the role of RNA exosome in resolving deleterious DNA/RNA hybrids arising from active enhancers. We have uncovered a distal divergent eRNA-expressing element (lncRNA-CSR) engaged in long-range DNA interactions and regulating IgH 3' regulatory region super-enhancer function. CRISPR-Cas9-mediated ablation of lncRNA-CSR transcription decreases its chromosomal looping-mediated association with the IgH 3' regulatory region super-enhancer and leads to decreased class switch recombination efficiency. We propose that the RNA exosome protects divergently transcribed lncRNA expressing enhancers by resolving deleterious transcription-coupled secondary DNA structures, while also regulating long-range super-enhancer chromosomal interactions important for cellular function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Embryonic Stem Cells / metabolism
  • Enhancer Elements, Genetic
  • Exosome Multienzyme Ribonuclease Complex / metabolism*
  • Gene Expression Regulation*
  • Genomic Instability
  • Heterochromatin / metabolism
  • Immunoglobulin Class Switching
  • Immunoglobulin Heavy Chains / genetics
  • Mice
  • RNA, Long Noncoding / metabolism*
  • Regulatory Sequences, Nucleic Acid


  • Heterochromatin
  • Immunoglobulin Heavy Chains
  • RNA, Long Noncoding
  • Exosome Multienzyme Ribonuclease Complex

Associated data

  • SRA/SRP042355