Functional Roles of Acetylated Histone Marks at Mouse Meiotic Recombination Hot Spots

ABSTRACT

Meiotic recombination initiates following the formation of DNA double-strand breaks (DSBs) by the Spo11 endonuclease early in prophase I, at discrete regions in the genome coined “hot spots.” In mammals, meiotic DSB site selection is directed in part by sequence-specific binding of PRDM9, a polymorphic histone H3 (H3K4Me3) methyltransferase. However, other chromatin features needed for meiotic hot spot specification are largely unknown. Here we show that the recombinogenic cores of active hot spots in mice harbor several histone H3 and H4 acetylation and methylation marks that are typical of open, active chromatin. Further, deposition of these open chromatin-associated histone marks is dynamic and is manifest at spermatogonia and/or pre-leptotene-stage cells, which facilitates PRDM9 binding and access for Spo11 to direct the formation of DSBs, which are initiated at the leptotene stage. Importantly, manipulating histone acetylase and deacetylase activities established that histone acetylation marks are necessary for both hot spot activity and crossover resolution. We conclude that there are functional roles for histone acetylation marks at mammalian meiotic recombination hot spots.

KEYWORDS:

• crossover
• double-strand break initiation
• histone acetylation
• meiotic recombination
• mouse meiosis

Supplemental material for this article may be found at https://doi.org/10.1128/MCB.00942-15.

ACKNOWLEDGMENTS

We are indebted to Pavel Khil (NIDDK/NIH), Matthew Pipkin (Scripps Florida), and David Shibata (University of Tennessee Health Science Center) for reviewing the manuscript, to Howard Petrie, Bivian Torres, and Kimberley Lowe (Scripps Florida Flow Cytometry Core) as well as Brandon Young and Bradley Long (Scripps Florida Genomics Core) for their technical advice and assistance, and to numerous colleagues for discussions and insights. We also thank R. Daniel Camerini-Otero (NIDDK/NIH) for providing Spo11 ^−/− mice.

We have no relevant conflicts of interest to declare.

This project was supported in part by funding from the State of Florida to Scripps Florida and to the H. Lee Moffitt Cancer Center & Research Institute, by monies from the Marie Mayer and PGA Women's Cancer Awareness Days Postdoctoral Fellowships in Cancer Biology, by NIH grant GM085079, and by Cancer Center support grant P30 CA076292 to the Moffitt Cancer Center.

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Funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.