Cited by 201RNA Research and SplicingGenomics and Chromatin DynamicsRNA regulation and disease

Noncoding RNA transcription targets AID to divergently transcribed loci in B cells

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Pefanis, Evangelos, Wang, Jiguang, Rothschild, Gerson, Lim, Junghyun, Chao, Jaime, Rabadan, Raul, Economides, Aris N., Basu, Uttiya·2014·Nature

Abstract

The vast majority of the mammalian genome has the potential to express noncoding RNA (ncRNA). The 11-subunit RNA exosome complex is the main source of cellular 3'-5' exoribonucleolytic activity and potentially regulates the mammalian noncoding transcriptome. Here we generated a mouse model in which the essential subunit Exosc3 of the RNA exosome complex can be conditionally deleted. Exosc3-deficient B cells lack the ability to undergo normal levels of class switch recombination and somatic hypermutation, two mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein activation-induced cytidine deaminase (AID). The transcriptome of Exosc3-deficient B cells has revealed the presence of many novel RNA exosome substrate ncRNAs. RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 base pairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at Igh in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. We propose that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity.

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  • Pathogenic variants in EXOSC3 cause pontocerebellar hypoplasia type 1B (PCH1B).

    “Pathogenic variants in EXOSC3, a noncatalytic subunit of the RNA exosome, cause pontocerebellar hypoplasia type 1B (PCH1B)”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]

    The Methods section describes engineering the mouse Exosc3 locus, and the Extended Data describe Exosc3-deficient B cells. Searches for pontocerebellar hypoplasia, PCH1B, and pathogenic EXOSC3 variants found no passage in our copy linking those variants to the disease. (LLM, conf=0.75)

    Experimental — accuracy not yet measured
  • PCH1B is characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction.

    “PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene15,18,21–23,25.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]

    The Methods (SHM) and Extended Data passages concern Exosc3 function in B cells, not PCH1B. Searches for PCH1B symptoms and EXOSC3-associated pontocerebellar hypoplasia found no passage in our copy addressing hypotonia, cerebellar atrophy, or motor neuron dysfunction. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • Variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F).

    “variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F)15–25.”

    From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]

    The Abstract identifies Exosc3 as an RNA exosome subunit, but discusses its role in mouse B cells, not pontocerebellar hypoplasia. Searches for PCH, pontocerebellar hypoplasia, and the specified gene–subtype links found no passage in our copy addressing the claimed disease associations. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Authors
Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., & Basu, U.
Affiliations
  • Columbia University (US)
  • Regeneron (United States) (US)
Corresponding author
Basu, Uttiya
Venue
Nature
Published
2014-08-06
Volume
514
Issue
7522
Pages
389-393
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W1987152324
Cited by
201
References
40
Citations by year
2026: 19 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 14 · 2021: 15 · 2020: 14 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 19 · 2014: 6
FWCI
8.48
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (1dp2od008651-01)
  • National Cancer Institute (U54CA121852, R01CA185486, R01CA179044)
  • National Institute of Allergy and Infectious Diseases (R01AI099195)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
RNA exosome, EXOSC3, activation-induced cytidine deaminase, AID, non-coding RNA, antisense transcription, divergent transcription, class switch recombination, somatic hypermutation, R-loops, genomic instability, chromosomal translocation, B cells, conditional knockout mice, transcription start sites, antibody diversity, 3'-5' exoribonuclease
MeSH terms
AICDA (Activation-Induced Cytidine Deaminase), Animals, B-Lymphocytes, Cytidine Deaminase, DNA, Single-Stranded, Female, Immunoglobulin Heavy Chains, Male, Nucleic Acid Hybridization, Substrate Specificity, Transcription, Genetic, Translocation, Genetic, RNA, Antisense, RNA-Binding Proteins, Genome, Immunoglobulin Class Switching, Base Pairing, RNA, Untranslated, Transcription Initiation Site, Somatic Hypermutation, Immunoglobulin, Genomic Instability, Mice, DNA Breaks, Double-Stranded, Exosomes, Exosome Multienzyme Ribonuclease Complex

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