title: Continuous Histone Replacement by Hira Is Essential for Normal Transcriptional Regulation and De Novo DNA Methylation during Mouse Oogenesis.
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.
authors.affiliation: Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Buhe
authors.initials: B
authors.lastname: Nashun
authors.affiliation: Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Peter W S
authors.initials: PW
authors.lastname: Hill
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Sebastien A
authors.initials: SA
authors.lastname: Smallwood
authors.affiliation: Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.affiliation: Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Amouroux
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clark
authors.affiliation: 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.
authors.forename: Vineet
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Medical Research Council Clinical Sciences Centre (MRC CSC), Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: Elodie
authors.initials: E
authors.lastname: Ndjetehe
authors.affiliation: Transgenic and Reproductive Techniques Laboratory, Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Pelczar
authors.affiliation: 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.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Festenstein
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB22 3AT, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Hajkova
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D005306:Fertilization; D005786:Gene Expression Regulation; D056488:Histone Chaperones / Q000235:genetics* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D009866:Oogenesis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C484187:Hira protein, mouse; D056488:Histone Chaperones; D006657:Histones; D014157:Transcription Factors