Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis
- University of Cambridge, United Kingdom
- University of Oxford, United Kingdom
- Science for Life Laboratory, Sweden
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.
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.
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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Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis
eLife 5:e20235.
https://doi.org/10.7554/eLife.20235
Further reading
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- Chromosomes and Gene Expression
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- Chromosomes and Gene Expression
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Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
