Cell-type-specific genomics reveals histone modification dynamics in mammalian meiosis

Kwan-Wood Gabriel Lam,Florencia Pratto,Gang Cheng,R Daniel Camerini-Otero,Kevin Brick

doi:10.1038/s41467-019-11820-7

Abstract

Meiosis is the specialized cell division during which parental genomes recombine to create genotypically unique gametes. Despite its importance, mammalian meiosis cannot be studied in vitro, greatly limiting mechanistic studies. In vivo, meiocytes progress asynchronously through meiosis and therefore the study of specific stages of meiosis is a challenge. Here, we describe a method for isolating pure sub-populations of nuclei that allows for detailed study of meiotic substages. Interrogating the H3K4me3 landscape revealed dynamic chromatin transitions between substages of meiotic prophase I, both at sites of genetic recombination and at gene promoters. We also leveraged this method to perform the first comprehensive, genome-wide survey of histone marks in meiotic prophase, revealing a heretofore unappreciated complexity of the epigenetic landscape at meiotic recombination hotspots. Ultimately, this study presents a straightforward, scalable framework for interrogating the complexities of mammalian meiosis.

Highlights

Meiosis is the specialized cell division during which parental genomes recombine to create genotypically unique gametes
Unique to meiosis is the formation of programmed DNA double-strand breaks (DSBs) that result in recombination between parental haplotypes and whose repair tethers homologous chromosomes at the first meiotic division
Meiotic DSB formation, repair and recombination occur in a continuum of substages known collectively as meiotic prophase I (MPI), and each stage is characterized by specific nuclear events[1]

Summary

Introduction

Meiosis is the specialized cell division during which parental genomes recombine to create genotypically unique gametes. Using chromatin immunoprecipitation followed by highthroughput sequencing (ChIP-Seq) on sorted populations of nuclei, we determined that Histone H3 Lysine 4 trimethylation (H3K4me3) varies from stage-to-stage at meiotic DSB hotspots, gene promoters and a vast number of heretofore unannotated sites. H3K4me[3] is of key biological interest in meiosis because it regulates multiple independent dynamic processes during MPI; H3K4me[3] is found at gene promoters and its presence correlates with active transcription[25,26], whereas PRDM9-mediated H3K4me[3] marks the future sites of meiotic DSBs genomewide[27,28].

Results

Conclusion