Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis
Buhe Nashun, Peter W.S. Hill, Sebastien A. Smallwood, Gopuraja Dharmalingam, Rachel Amouroux, Stephen J. Clark, Vineet Sharma, Elodie Ndjetehe, Pawel Pelczar6, Richard J. Festenstein, Gavin Kelsey, Petra Hajkovacorrespondenceemail
6Present address: TMCF, University of Basel, Mattenstrasse 24a, 4058 Basel, Switzerland
Publication stage: In Press Corrected Proof
Open Access
Highlights
• Histone H3/H4 replacement is continuous and mediated by Hira during mouse oogenesis
• Loss of Hira results in chromatin abnormalities and extensive oocyte loss
• Hira depletion reduces histone load, which prevents normal transcriptional regulation
• Hira-mediated histone replacement is required for normal 5mC deposition in oocytes
Summary
The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.
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