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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Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.