title: RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity.
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.
authors.affiliation: 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.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pefanis
authors.affiliation: Department of Biomedical Informatics and Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Gerson
authors.initials: G
authors.lastname: Rothschild
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Lim
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kazadi
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Sun
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Federation
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Chao
authors.affiliation: Department of Biomedical Informatics and Department of Systems Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Elliott
authors.affiliation: Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong 250061, China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Liu
authors.affiliation: Regeneron Pharmaceuticals and Regeneron Genetics Center, Tarrytown, NY 10591, USA.
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: 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.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: ub2121@cumc.columbia.edu.
authors.forename: Uttiya
authors.initials: U
authors.lastname: Basu
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D063326:Exosome Multienzyme Ribonuclease Complex / Q000378:metabolism*; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006570:Heterochromatin / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D051379:Mice; D062085:RNA, Long Noncoding / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D006570:Heterochromatin; D007143:Immunoglobulin Heavy Chains; D062085:RNA, Long Noncoding; D063326:Exosome Multienzyme Ribonuclease Complex