A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis
Abstract
PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.
Data availability
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Mapping PRDM9 binding and its effects in transfected HEK293T cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE99407).
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Recombination initiation maps of individual human genomesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE59836).
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ChIP-exo of human KRAB-ZNFs transduced in HEK 293T cells and KAP1 in hES H1 cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE78099).
Article and author information
Author details
Funding
Wellcome (Investigator Award 098387/Z/12/Z)
- Simon R Myers
Cancer Research UK (Career Development Fellowship C52690/A19270)
- J Ross Chapman
Howard Hughes Medical Institute (Gilliam Fellowship for Advanced Study)
- Nicolas Altemose
Medical Research Council (Grant MR/L009609/1)
- A Radu Aricescu
Foreign and Commonwealth Office (Marshall Scholarship)
- Nicolas Altemose
Wellcome (Core Award 090532/Z/09/Z)
- Nicolas Altemose
- Nudrat Noor
- Emmanuelle Bitoun
- J Ross Chapman
- A Radu Aricescu
- Simon R Myers
Wellcome (DPhil Studentship 086817/Z/08/Z)
- Nudrat Noor
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Molly Przeworski, Columbia University, United States
Version history
- Received: May 5, 2017
- Accepted: October 24, 2017
- Accepted Manuscript published: October 26, 2017 (version 1)
- Version of Record published: November 28, 2017 (version 2)
Copyright
© 2017, Altemose 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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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.