RNA Exosome-Regulated Long Non-Coding RNA Transcription Controls Super-Enhancer Activity
Open accessAbstract
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.
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Many transcripts differentially expressed in all five datasets were noncoding RNAs, which are well established targets for the RNA exosome and can include PROMPTs, antisense transcripts, and long noncoding RNAs.
“Many of the transcripts that were differentially expressed in all five datasets were noncoding RNAs, which are well established to be targets for the RNA exosome and can include PROMPTs, antisense (AS) transcripts, and long noncoding RNAs (lncRNAs) as shown in Fig. 2B61–67.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [64]
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- Authors
- Pefanis, E., Wang, J., Rothschild, G., Lim, J., Kazadi, D., Sun, J., Federation, A., Chao, J., Elliott, O., Liu, Z.-P., Economides, A. N., Bradner, J. E., Rabadan, R., & Basu, U.
- Affiliations
- Regeneron (United States) (US)
- Columbia University (US)
- Harvard University (US)
- Shandong University (CN)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Basu, Uttiya
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 161
- Issue
- 4
- Pages
- 774-789
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4428671
- OpenAlex
- W1635346580
- Cited by
- 464
- References
- 14
- Citations by year
- 2026: 26 · 2025: 36 · 2024: 33 · 2023: 35 · 2022: 36 · 2021: 63 · 2020: 52 · 2019: 43 · 2018: 41 · 2017: 48 · 2016: 31 · 2015: 20
- FWCI
- 14.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (1DP2OD008651-01)
- National Institute of Allergy and Infectious Diseases (1R01AI099195-01A1, 1R01CA179044-01A1, 1R01CA185486-01, 1U54CA121852-05, F31AI098411-01A1)
- Leukemia and Lymphoma Society
- Irma T. Hirschl Trust
- 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 › RNA Research and Splicing
- Keywords
- RNA exosome, long non-coding RNA, enhancer RNA, super-enhancers, R-loops, RNA-DNA hybrids, divergent transcription, class switch recombination, chromatin looping, EXOSC3, B cells, embryonic stem cells, conditional mutagenesis
- MeSH terms
- Animals, B-Lymphocytes, Enhancer Elements, Genetic, Gene Expression Regulation, Heterochromatin, Immunoglobulin Heavy Chains, Regulatory Sequences, Nucleic Acid, Immunoglobulin Class Switching, Genomic Instability, Mice, Embryonic Stem Cells, RNA, Long Noncoding, Exosome Multienzyme Ribonuclease Complex
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