Successful reproduction requires an oocyte competent to sustain early embryo development. By the end of oogenesis, the oocyte has entered a transcriptionally silenced state, the mechanisms and significance of which remain poorly understood. Histone H3.3, a histone H3 variant, has unique cell cycle-independent functions in chromatin structure and gene expression. Here, we have characterised the H3.3 chaperone Hira/Cabin1/Ubn1 complex, showing that loss of function of any of these subunits causes early embryogenesis failure in mouse. Transcriptome and nascent RNA analyses revealed that transcription is aberrantly silenced in mutant oocytes. Histone marks, including H3K4me3 and H3K9me3, are reduced and chromatin accessibility is impaired in Hira/Cabin1 mutants. Misregulated genes in mutant oocytes include Zscan4d, a two-cell specific gene involved in zygote genome activation. Overexpression of Zscan4 in the oocyte partially recapitulates the phenotypes of Hira mutants and Zscan4 knockdown in Cabin1 mutant oocytes partially restored their developmental potential, illustrating that temporal and spatial expression of Zscan4 is fine-tuned at the oocyte-to-embryo transition. Thus, the H3.3 chaperone Hira complex has a maternal effect function in oocyte developmental competence and embryogenesis, through modulating chromatin condensation and transcriptional quiescence.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• chromatin metabolismus   MeSH
• embryonální vývoj genetika   MeSH
• genový knockdown MeSH
• histonové chaperony genetika   metabolismus   MeSH
• histony metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• oocyty růst a vývoj   metabolismus   MeSH
• oogeneze genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• signální transdukce genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• zygota metabolismus   MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

PURPOSE: There is strong epidemiologic evidence indicating that estrogens may not be the sole steroid drivers of breast cancer. We hypothesize that abundant adrenal androgenic steroid precursors, acting via the androgen receptor (AR), promote an endocrine-resistant breast cancer phenotype. EXPERIMENTAL DESIGN: AR was evaluated in a primary breast cancer tissue microarray (n = 844). Androstenedione (4AD) levels were evaluated in serum samples (n = 42) from hormone receptor-positive, postmenopausal breast cancer. Levels of androgens, progesterone, and estradiol were quantified using LC/MS-MS in serum from age- and grade-matched recurrent and nonrecurrent patients (n = 6) before and after aromatase inhibitor (AI) therapy (>12 months). AR and estrogen receptor (ER) signaling pathway activities were analyzed in two independent AI-treated cohorts. RESULTS: AR protein expression was associated with favorable progression-free survival in the total population (Wilcoxon, P < 0.001). Pretherapy serum samples from breast cancer patients showed decreasing levels of 4AD with age only in the nonrecurrent group (P < 0.05). LC/MS-MS analysis of an AI-sensitive and AI-resistant cohort demonstrated the ability to detect altered levels of steroids in serum of patients before and after AI therapy. Transcriptional analysis showed an increased ratio of AR:ER signaling pathway activities in patients failing AI therapy (t test P < 0.05); furthermore, 4AD mediated gene changes associated with acquired AI resistance. CONCLUSIONS: This study highlights the importance of examining the therapeutic consequences of the steroid microenvironment and demonstrable receptor activation using indicative gene expression signatures.

• MeSH
• androgenní receptory fyziologie   MeSH
• androstendion krev   fyziologie   MeSH
• chemorezistence MeSH
• inhibitory aromatasy terapeutické užití   MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buňky kultivované MeSH
• nádory prsu krev   farmakoterapie   etiologie   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Regulation of translation is essential for the diverse biological processes involved in development. Particularly, mammalian oocyte development requires the precisely controlled translation of maternal transcripts to coordinate meiotic and early embryo progression while transcription is silent. It has been recently reported that key components of mRNA translation control are short and long noncoding RNAs (ncRNAs). We found that the ncRNABrain cytoplasmic 1 (BC1) has a role in the fully grown germinal vesicle (GV) mouse oocyte, where is highly expressed in the cytoplasm associated with polysomes. Overexpression of BC1 in GV oocyte leads to a minute decrease in global translation with a significant reduction of specific mRNA translation via interaction with the Fragile X Mental Retardation Protein (FMRP). BC1 performs a repressive role in translation only in the GV stage oocyte without forming FMRP or Poly(A) granules. In conclusion, BC1 acts as the translational repressor of specific mRNAs in the GV stage via its binding to a subset of mRNAs and physical interaction with FMRP. The results reported herein contribute to the understanding of the molecular mechanisms of developmental events connected with maternal mRNA translation.

• MeSH
• cytoplazma genetika   metabolismus   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• nekódující RNA genetika   MeSH
• oocyty cytologie   fyziologie   MeSH
• oogeneze * MeSH
• polyribozomy genetika   metabolismus   MeSH
• proteosyntéza * MeSH
• RNA malá cytoplazmatická genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH