title: Major chromatin remodeling in the germinal vesicle (GV) of mammalian oocytes is dispensable for global transcriptional silencing but required for centromeric heterochromatin function.
abstract: Global silencing of transcriptional activity in the oocyte genome occurs just before the resumption of meiosis and is a crucial developmental transition at the culmination of oogenesis. Transcriptionally quiescent oocytes rely on stored maternal transcripts to sustain the completion of meiosis, fertilization, and early embryonic cleavage stages. Thus, the timing of silencing is key for successful embryo development. Yet, the cellular and molecular pathways coordinating dynamic changes in large-scale chromatin structure with the onset of transcriptional repression are poorly understood. Here, oocytes obtained from nucleoplasmin 2 knockout (Npm2-/-) mice were used to investigate the relationship between transcriptional repression and chromatin remodeling in the germinal vesicle (GV) of mammalian oocytes. Although temporally linked, global silencing of transcription and chromatin remodeling in the oocyte genome can be experimentally dissociated and therefore must be regulated through distinct pathways. Detection of centromeric heterochromatin DNA sequences with a mouse pan-centromeric chromosome paint revealed that most centromeres are found in close apposition with the nucleolus in transcriptionally quiescent oocytes and therefore constitute an important component of the perinucleolar heterochromatin rim or karyosphere. Pharmacological inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) revealed that HDACs are essential for large-scale chromatin remodeling in the GV. Importantly, the specialized nuclear architecture acquired upon transcriptional repression is essential for meiotic progression as interference with global deacetylation and partial disruption of the karyosphere resulted in a dramatic increase in the proportion of oocytes exhibiting abnormal meiotic chromosome and spindle configuration. These results indicate that the unique chromatin remodeling mechanism in oocytes may be specifically related to meiotic cell division in female mammals.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA. rfuente@vet.upenn.edu
authors.forename: Rabindranath
authors.initials: R
authors.lastname: De La Fuente
authors.forename: Maria M
authors.initials: MM
authors.lastname: Viveiros
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Burns
authors.forename: Eli Y
authors.initials: EY
authors.lastname: Adashi
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
authors.forename: John J
authors.initials: JJ
authors.lastname: Eppig
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002503:Centromere / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology*; D020223:Chromosome Painting; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006570:Heterochromatin / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000502:physiology*
chemical_list: D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A