Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis
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.
Data availability
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Chip-Seq analysis of human chromosome 21 after its passage through either the female or male mouse germlinePublicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4913).
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BioCAP-Seq analysis of human chromosome 21 after its passage through either the mouse male germlinePublicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4930).
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RNA-Seq in liver of Tc1 mice carrying human chromosome 21 passaged through either the female or male germlinePublicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4912).
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E-MTAB-1104 - ChIP-seq of human and transgenic mouse adult liver, testes & kidney tissue to investigate epigenetic comparisonPublicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-1104).
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E-MTAB-2633 - ChIP-Seq analysis of regulatory evolution in 20 mammalsPublicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-2633).
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E-TABM-722 - ChIP-seq of Canis familiaris, Gallus gallus, Mus musculus, Homo sapiens, Monodelphis domestica to investigate CEBPA and HNF4a binding in five vertebratesPublicly available at the EBI European Nucleotide Archive (accession no: E-TABM-722).
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An evolutionarily conserved DNA-encoded logic shapes CpG island formationPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE72208).
Article and author information
Author details
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.
Reviewing Editor
- Edith Heard, Institut Curie, France
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.
Version history
- Received: August 1, 2016
- Accepted: November 14, 2016
- Accepted Manuscript published: November 18, 2016 (version 1)
- Accepted Manuscript updated: November 22, 2016 (version 2)
- 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
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Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.
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Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.