1. Chromosomes and Gene Expression
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Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis

  1. Christina Ernst
  2. Jeremy Pike
  3. Sarah J Aitken
  4. Hannah K Long
  5. Nils Eling
  6. Lovorka Stojic
  7. Frances Connor
  8. Tim F Rayner
  9. Margus Lukk
  10. Robert J Klose
  11. Claudia Kutter
  12. Duncan T Odom  Is a corresponding author
  1. University of Cambridge, United Kingdom
  2. University of Oxford, United Kingdom
  3. Science for Life Laboratory, Sweden
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Cite this article as: eLife 2016;5:e20235 doi: 10.7554/eLife.20235

Abstract

Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.

Article and author information

Author details

  1. Christina Ernst

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3569-2209
  2. Jeremy Pike

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Sarah J Aitken

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Hannah K Long

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Nils Eling

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  6. Lovorka Stojic

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  7. Frances Connor

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  8. Tim F Rayner

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  9. Margus Lukk

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  10. Robert J Klose

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8726-7888
  11. Claudia Kutter

    Science for Life Laboratory, Stockholm, Sweden
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8047-0058
  12. Duncan T Odom

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    Duncan.Odom@cruk.cam.ac.uk
    Competing interests
    Duncan T Odom, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6201-5599

Funding

Cancer Research UK (A20412)

  • Christina Ernst
  • Sarah J Aitken
  • Nils Eling
  • Frances Connor
  • Tim F Rayner
  • Margus Lukk
  • Claudia Kutter
  • Duncan T Odom

European Research Council (615584)

  • Duncan T Odom

Wellcome (098024/Z/11/Z)

  • Robert J Klose

Wellcome (106563/Z/14/A)

  • Sarah J Aitken

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This investigation was approved by the Animal Welfare and Ethics Review Board and followed the Cambridge Institute guidelines for the use of animals in experimental studies under Home Office license PPL 70/7535.

Human subjects: Previously published human data from Ward et al. 2013 were used for comparisons in this study.

Reviewing Editor

  1. Edith Heard, Institut Curie, France

Publication history

  1. Received: August 1, 2016
  2. Accepted: November 14, 2016
  3. Accepted Manuscript published: November 18, 2016 (version 1)
  4. Accepted Manuscript updated: November 22, 2016 (version 2)
  5. Version of Record published: December 16, 2016 (version 3)

Copyright

© 2016, Ernst 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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Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
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    One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived of oxygen. To study inter-individual differences in response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels in four culturing conditions that correspond to normoxia, hypoxia, and short- or long-term re-oxygenation. We characterized thousands of gene regulatory changes as the cells transition between conditions. Using available genotypes, we identified 1,573 genes with a cis expression quantitative locus (eQTL) in at least one condition, as well as 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of genes with dynamic eQTLs is associated with complex traits and disease. Our data demonstrate how dynamic genetic effects on gene expression, which are likely relevant for disease, can be uncovered under stress.

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
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    R-loops are three-stranded nucleic acid structures with essential roles in many nuclear processes. However, their unchecked accumulation is associated with genome instability and is observed in neurodevelopmental diseases and cancers. Genome-wide profiling of R-loops in normal and diseased cells can help identify locations of pathogenic R-loops and advance efforts to attenuate them. We present an antibody-independent R-loop detection strategy, BisMapR, that combines nuclease-based R-loop isolation with non-denaturing bisulfite chemistry to produce genome-wide profiles that retain strand information. BisMapR achieves greater resolution and is faster than existing strand-specific R-loop profiling strategies. In mouse embryonic stem cells, we apply BisMapR to find that gene promoters form R-loops in both directions and uncover a subset of active enhancers that, despite being bidirectionally transcribed, form R-loops exclusively on one strand. BisMapR reveals a previously unnoticed feature of active enhancers and provides a tool to systematically examine their mechanisms in gene expression.