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Systematic genetic and proteomic screens identify yeast H2BK37 and mammalian H2BK34 methylation as an evolutionary conserved meiotic mark

ABSTRACT: Gametes are highly differentiated cells specialized to carry and protect the parental genetic information. Their chromatin organization is highly compacted and the establishment of this nuclear structure involves many chromatin processes. Technical difficulties exclude the analysis of precise histone mutations during mouse spermatogenesis. The model organism Saccharomyces cerevisiae possesses a differentiation pathway named sporulation with striking similarities with mammalian spermatogenesis. This study took advantage of this yeast pathway and performed a systematic mutational screen on the histone H2A and H2B, revealing the residues which are essential for the formation of spores. Many of them are localized on the lateral side of the nucleosome, highlighting the importance of this surface for meiotic divisions and the formation of spores. Second, histones have been purified at different stages of sporulation and their post-translational modifications analyzed by mass spectrometry. Fifteen new sites of acetylation, methylation or phosphorylation have been identified on the core histones in yeast. Methylation of H2BK37 appears to be a new meiotic mark and is important for Rad51 action. Thus, this modification is conserved during mammalian spermatogenesis when it is found enriched during meiosis. Altogether, our results demonstrate that a combination of genetic and proteomic approaches applied to yeast sporulation can reveal new aspects of chromatin signaling pathways during mammalian spermatogenesis.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Delphine PFLIEGER

LAB HEAD: Virginie Brun

PROVIDER: PXD006213 | Pride | 2020-09-21

REPOSITORIES: Pride

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Systematic genetic and proteomic screens during gametogenesis identify H2BK34 methylation as an evolutionary conserved meiotic mark.

Crespo Marion M Luense Lacey J LJ Arlotto Marie M Hu Jialei J Dorsey Jean J García-Oliver Encar E Shah Parisha P PP Pflieger Delphine D Berger Shelley L SL Govin Jérôme J

Epigenetics & chromatin 20200915 1

<h4>Background</h4>Gametes are highly differentiated cells specialized to carry and protect the parental genetic information. During male germ cell maturation, histone proteins undergo distinct changes that result in a highly compacted chromatin organization. Technical difficulties exclude comprehensive analysis of precise histone mutations during mammalian spermatogenesis. The model organism Saccharomyces cerevisiae possesses a differentiation pathway termed sporulation which exhibits striking ...[more]

PMID: 32933557

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Project description:Ray2013 - Meiotic initiation in S. cerevisiae A mathematical representation of early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signalling molecules for regulating protein activities, is described here This model is described in the article: Dynamic modeling of yeast meiotic initiation. Ray D, Su Y, Ye P. BMC Syst Biol. 2013 May 1;7:37 Abstract: BACKGROUND: Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities. RESULTS: The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state. CONCLUSIONS: By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity. This model is hosted on BioModels Database and identified by: BIOMD0000000626 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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