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

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

Author information

1
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Regeneron Pharmaceuticals and Regeneron Genetics Center, Tarrytown, NY 10591, USA.
2
Department of Biomedical Informatics and Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
3
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
4
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
5
Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
6
Regeneron Pharmaceuticals and Regeneron Genetics Center, Tarrytown, NY 10591, USA.
7
Department of Biomedical Informatics and Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: rr2579@cumc.columbia.edu.
8
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: ub2121@cumc.columbia.edu.

Abstract

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.

PMID:
25957685
PMCID:
PMC4428671
DOI:
10.1016/j.cell.2015.04.034
[Indexed for MEDLINE]
Free PMC Article

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