Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription
- CNRS, France
- MRC London Institute of Medical Sciences (LMS), United Kingdom
- European Molecular Biology Laboratory, Germany
Abstract
Condensins are genome organisers that shape chromosomes and promote their accurate transmission. Several studies have also implicated condensins in gene expression, although any mechanisms have remained enigmatic. Here, we report on the role of condensin in gene expression in fission and budding yeasts. In contrast to previous studies, we provide compelling evidence that condensin plays no direct role in the maintenance of the transcriptome, neither during interphase nor during mitosis. We further show that the changes in gene expression in post-mitotic fission yeast cells that result from condensin inactivation are largely a consequence of chromosome missegregation during anaphase, which notably depletes the RNA-exosome from daughter cells. Crucially, preventing karyotype abnormalities in daughter cells restores a normal transcriptome despite condensin inactivation. Thus, chromosome instability, rather than a direct role of condensin in the transcription process, changes gene expression. This knowledge challenges the concept of gene regulation by canonical condensin complexes.
Data availability
RNA-seq data are accessible from the Gene Expression Omnibus (GEO) database under the accession number GSE112281.Microarrays data are available as supplemental table in excel format
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Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcriptionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE112281).
Article and author information
Author details
Sara Cuylen-Haering
Christian H Haering
Funding
Centre National de la Recherche Scientifique
- Pascal Bernard
Agence Nationale de la Recherche (ANR-15-CE12-0002-01)
- Xavier Robellet
- Pascal Bernard
Fondation ARC pour la Recherche sur le Cancer (PJA 20151203343)
- Pascal Bernard
Ligue Régionale Contre le Cancer - comité du Rhône
- Pascal Bernard
Medical Research Council
- Xi-Ming Sun
- Samuel Marguerat
European Molecular Biology Laboratory
- Sara Cuylen-Haering
- Sandra Clauder-Münster
- Lars Steinmetz
- Christian H Haering
Fondation pour la Recherche Médicale (FDT20170437039)
- Clémence Hocquet
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Hocquet et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Condensin controls cellular RNA levels through the accurate segregation of chromosomes instead of directly regulating transcription
eLife 7:e38517.
https://doi.org/10.7554/eLife.38517
Further reading
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- Chromosomes and Gene Expression
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Pathogenic variants in subunits of RNA polymerase (Pol) III cause a spectrum of Polr3-related neurodegenerative diseases including 4H leukodystrophy. Disease onset occurs from infancy to early adulthood and is associated with a variable range and severity of neurological and non-neurological features. The molecular basis of Polr3-related disease pathogenesis is unknown. We developed a postnatal whole-body mouse model expressing pathogenic Polr3a mutations to examine the molecular mechanisms by which reduced Pol III transcription results primarily in central nervous system phenotypes. Polr3a mutant mice exhibit behavioral deficits, cerebral pathology and exocrine pancreatic atrophy. Transcriptome and immunohistochemistry analyses of cerebra during disease progression show a reduction in most Pol III transcripts, induction of innate immune and integrated stress responses and cell-type-specific gene expression changes reflecting neuron and oligodendrocyte loss and microglial activation. Earlier in the disease when integrated stress and innate immune responses are minimally induced, mature tRNA sequencing revealed a global reduction in tRNA levels and an altered tRNA profile but no changes in other Pol III transcripts. Thus, changes in the size and/or composition of the tRNA pool have a causal role in disease initiation. Our findings reveal different tissue- and brain region-specific sensitivities to a defect in Pol III transcription.
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- Biochemistry and Chemical Biology
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The mRNA 5'-cap structure removal by the decapping enzyme DCP2 is a critical step in gene regulation. While DCP2 is the catalytic subunit in the decapping complex, its activity is strongly enhanced by multiple factors, particularly DCP1, which is the major activator in yeast. However, the precise role of DCP1 in metazoans has yet to be fully elucidated. Moreover, in humans, the specific biological functions of the two DCP1 paralogs, DCP1a and DCP1b, remain largely unknown. To investigate the role of human DCP1, we generated cell lines that were deficient in DCP1a, DCP1b, or both to evaluate the importance of DCP1 in the decapping machinery. Our results highlight the importance of human DCP1 in decapping process and show that the EVH1 domain of DCP1 enhances the mRNA-binding affinity of DCP2. Transcriptome and metabolome analyses outline the distinct functions of DCP1a and DCP1b in human cells, regulating specific endogenous mRNA targets and biological processes. Overall, our findings provide insights into the molecular mechanism of human DCP1 in mRNA decapping and shed light on the distinct functions of its paralogs.
