Epigenetic Dysregulation of Mammalian Male Meiosis Caused by Interference of Recombination and Synapsis.

Roberto De La Fuente,Abrahan Hernández-Hernández,R Daniel Camerini-Otero,Florencia Pratto,Jesús Page,Alberto Viera,Anna Kouznetsova,María Teresa Parra,Pablo López-Jiménez,Rocío Gómez,Marcia Manterola

doi:10.3390/cells10092311

Abstract

Meiosis involves a series of specific chromosome events, namely homologous synapsis, recombination, and segregation. Disruption of either recombination or synapsis in mammals results in the interruption of meiosis progression during the first meiotic prophase. This is usually accompanied by a defective transcriptional inactivation of the X and Y chromosomes, which triggers a meiosis breakdown in many mutant models. However, epigenetic changes and transcriptional regulation are also expected to affect autosomes. In this work, we studied the dynamics of epigenetic markers related to chromatin silencing, transcriptional regulation, and meiotic sex chromosome inactivation throughout meiosis in knockout mice for genes encoding for recombination proteins SPO11, DMC1, HOP2 and MLH1, and the synaptonemal complex proteins SYCP1 and SYCP3. These models are defective in recombination and/or synapsis and promote apoptosis at different stages of progression. Our results indicate that impairment of recombination and synapsis alter the dynamics and localization pattern of epigenetic marks, as well as the transcriptional regulation of both autosomes and sex chromosomes throughout prophase-I progression. We also observed that the morphological progression of spermatocytes throughout meiosis and the dynamics of epigenetic marks are processes that can be desynchronized upon synapsis or recombination alteration. Moreover, we detected an overlap of early and late epigenetic signatures in most mutants, indicating that the normal epigenetic transitions are disrupted. This can alter the transcriptional shift that occurs in spermatocytes in mid prophase-I and suggest that the epigenetic regulation of sex chromosomes, but also of autosomes, is an important factor in the impairment of meiosis progression in mammals.

Highlights

During the prophase of the first meiotic division, homologous chromosomes undergo a series of distinctive processes: pairing, synapsis, and recombination
To analyze the epigenetic consequences produced when DNA recombination and synapsis are interfered in meiosis, we studied Spo11-/, Dmc1-/, Hop2-/- and Mlh1-/- mice, which present alterations at different steps of the recombination pathway, and Sycp1-/- and
The dynamics of H3K9me3 localization reveals that at the beginning of meiosis the chromatin presents a conspicuous accumulation of an epigenetic factor involved in transcription downregulation that is subsequently removed as prophase-I progresses

Summary

Introduction

During the prophase of the first meiotic division, homologous chromosomes undergo a series of distinctive processes: pairing, synapsis, and recombination. The occurrence of these events is dependent on cytological and molecular mechanisms that have been intensively studied in the last few decades [1]. To pairing and synapsis, homologous chromosomes undergo meiotic recombination In organism such as yeast, plants, and mammals, recombination is initiated during leptotene with the induction of hundreds of DNA double strand breaks (DSBs). This requires the action of the SPO11–

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