MLL2 Is Required in Oocytes for Bulk Histone 3 Lysine 4 Trimethylation and Transcriptional Silencing

Claudia V Andreu-Vieyra,A Francis Stewart,Konstantinos Anastassiadis,Stefan Glaser,Julio E Agno,Martin M Matzuk,Ruihong Chen,Wolf Reik

doi:10.1371/journal.pbio.1000453

Claudia V Andreu-Vieyra, A Francis Stewart + Show 6 more

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https://doi.org/10.1371/journal.pbio.1000453

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Abstract

Author SummaryIt is well established that gametes and early mammalian embryos undergo extensive epigenetic changes, which are changes in phenotype or gene expression that do not entail changes in DNA sequence. However, the machinery responsible for epigenetic modification in these situations is poorly understood. In mice, we conditionally deleted the histone 3 lysine 4 (H3K4) methyltransferase Mll2, an enzyme that alters DNA structure and packaging, either in gametes or in somatic cells of the ovary and also produced a mouse hypomorph expressing low levels of MLL2. We show that MLL2 is required in oocytes during gametogenesis and is also needed as a maternally derived factor during early development. Oocytes deficient in Mll2 display decreased methylation of H3K4 (H3K4me3) and show abnormal maturation and gene expression, in particular of pro-apoptotic factors. In addition, we demonstrate that embryonic genome activation is compromised in the absence of Mll2. Together our results identify MLL2 as one of the key players in the epigenetic reprogramming required for female fertility in the mouse.

Highlights

Mammalian epigenomes are fundamentally reprogrammed during gametogenesis and pre-implantation development to establish the ground state of pluripotency in the epiblast cells of the blastocyst [1,2,3,4,5]
We show that MLL2 is required in oocytes during gametogenesis and is needed as a maternally derived factor during early development
Together our results identify MLL2 as one of the key players in the epigenetic reprogramming required for female fertility in the mouse

Summary

Introduction

Mammalian epigenomes are fundamentally reprogrammed during gametogenesis and pre-implantation development to establish the ground state of pluripotency in the epiblast cells of the blastocyst [1,2,3,4,5]. Epigenetic reprogramming of the maternal genome occurs during oogenesis. Transcription of the oocyte genome serves to establish the reservoirs of maternal components that are required for the first stages of embryonic development [8]. Global transcriptional silencing in oocytes is thought to be required for the efficient resumption and completion of meiosis [9] and occurs parallel to large-scale chromatin condensation and rearrangement around the nucleolus to establish a chromatin configuration termed SN (surrounded nucleolus) [1,10,11]. Previous studies showed that global transcriptional silencing can occur without the establishment of the SN state [1,12]. Further studies indicated that both the acquisition of the SN configuration and transcriptional silencing are pre-requisites to achieve full embryonic developmental potential [13,14]

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