Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells
- 1 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 53 (2), 230-242
- https://doi.org/10.1038/s41588-020-00772-0
Abstract
Noncoding RNAs are exquisitely titrated by the cellular RNA surveillance machinery for regulating diverse biological processes. The RNA exosome, the predominant 3′ RNA exoribonuclease in mammalian cells, is composed of nine core and two catalytic subunits. Here, we developed a mouse model with a conditional allele to study the RNA exosome catalytic subunit DIS3. In DIS3-deficient B cells, integrity of the immunoglobulin heavy chain (Igh) locus in its topologically associating domain is affected, with accumulation of DNA-associated RNAs flanking CTCF-binding elements, decreased CTCF binding to CTCF-binding elements and disorganized cohesin localization. DIS3-deficient B cells also accumulate activation-induced cytidine deaminase–mediated asymmetric nicks, altering somatic hypermutation patterns and increasing microhomology-mediated end-joining DNA repair. Altered mutation patterns and Igh architectural defects in DIS3-deficient B cells lead to decreased class-switch recombination but increased chromosomal translocations. Our observations of DIS3-mediated architectural regulation at the Igh locus are reflected genome wide, thus providing evidence that noncoding RNA processing is an important mechanism for controlling genome organization.Keywords
Funding Information
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (1R01AI099195)
- Leukemia and Lymphoma Society
- European Molecular Biology Organization (ALTF 906-2015)
This publication has 84 references indexed in Scilit:
- Fast gapped-read alignment with Bowtie 2Nature Methods, 2012
- RNase H and Multiple RNA Biogenesis Factors Cooperate to Prevent RNA:DNA Hybrids from Generating Genome InstabilityMolecular Cell, 2011
- Genome-wide Translocation Sequencing Reveals Mechanisms of Chromosome Breaks and Rearrangements in B CellsCell, 2011
- Translocation-Capture Sequencing Reveals the Extent and Nature of Chromosomal Rearrangements in B LymphocytesCell, 2011
- PROMoter uPstream Transcripts share characteristics with mRNAs and are produced upstream of all three major types of mammalian promotersNucleic Acids Research, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- Activation-Induced Cytidine Deaminase Targets DNA at Sites of RNA Polymerase II Stalling by Interaction with Spt5Cell, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Circos: An information aesthetic for comparative genomicsGenome Research, 2009
- DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytesNature, 2008