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.
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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Further reading
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RNA interference (RNAi) is a conserved pathway that utilizes Argonaute proteins and their associated small RNAs to exert gene regulatory function on complementary transcripts. While the majority of germline-expressed RNAi proteins reside in perinuclear germ granules, it is unknown whether and how RNAi pathways are spatially organized in other cell types. Here, we find that the small RNA biogenesis machinery is spatially and temporally organized during Caenorhabditis elegans embryogenesis. Specifically, the RNAi factor, SIMR-1, forms visible concentrates during mid-embryogenesis that contain an RNA-dependent RNA polymerase, a poly-UG polymerase, and the unloaded nuclear Argonaute protein, NRDE-3. Curiously, coincident with the appearance of the SIMR granules, the small RNAs bound to NRDE-3 switch from predominantly CSR-class 22G-RNAs to ERGO-dependent 22G-RNAs. NRDE-3 binds ERGO-dependent 22G-RNAs in the somatic cells of larvae and adults to silence ERGO-target genes; here we further demonstrate that NRDE-3-bound, CSR-class 22G-RNAs repress transcription in oocytes. Thus, our study defines two separable roles for NRDE-3, targeting germline-expressed genes during oogenesis to promote global transcriptional repression, and switching during embryogenesis to repress recently duplicated genes and retrotransposons in somatic cells, highlighting the plasticity of Argonaute proteins and the need for more precise temporal characterization of Argonaute-small RNA interactions.
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