Format

Send to

Choose Destination
Mol Cell. 2015 Nov 19;60(4):611-25. doi: 10.1016/j.molcel.2015.10.010. Epub 2015 Nov 5.

Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.

Author information

1
Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
2
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
3
Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK; Department of Medicine, Division of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
4
Transgenic and Reproductive Techniques Laboratory, Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
5
Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB22 3AT, UK.
6
Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK. Electronic address: petra.hajkova@csc.mrc.ac.uk.

Abstract

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.

PMID:
26549683
PMCID:
PMC4672152
DOI:
10.1016/j.molcel.2015.10.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center