RESUMO
For cells to initiate and sustain a differentiated state, it is necessary that a 'memory' of this state is transmitted through mitosis to the daughter cells1-3. Mammalian switch/sucrose non-fermentable (SWI/SNF) complexes (also known as Brg1/Brg-associated factors, or BAF) control cell identity by modulating chromatin architecture to regulate gene expression4-7, but whether they participate in cell fate memory is unclear. Here we provide evidence that subunits of SWI/SNF act as mitotic bookmarks to safeguard cell identity during cell division. The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but are bound to promoters during mitosis, and we show that this binding is required for appropriate reactivation of bound genes after mitotic exit. Ablation of SMARCE1 during a single mitosis in mouse embryonic stem cells is sufficient to disrupt gene expression, impair the occupancy of several established bookmarks at a subset of their targets and cause aberrant neural differentiation. Thus, SWI/SNF subunit SMARCE1 has a mitotic bookmarking role and is essential for heritable epigenetic fidelity during transcriptional reprogramming.
Assuntos
Diferenciação Celular , Proteínas Cromossômicas não Histona , Epigênese Genética , Mitose , Animais , Camundongos , Diferenciação Celular/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Mitose/genética , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Subunidades Proteicas/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Elementos Facilitadores Genéticos/genética , Regiões Promotoras Genéticas/genética , Divisão Celular/genética , Epigênese Genética/genéticaRESUMO
Ovarian cells are critical for reproduction and steroidogenesis, which are functions that can be impacted by exposure to xenobiotics. As in other extra-hepatic tissues, biotransformation events may occur at the ovarian level. Such metabolic events deserve interest, notably as they may modulate the overall exposure and toxicity of xenobiotics. In this study, the comparative metabolic fate of two bisphenols was investigated in ovarian cells. Bisphenol A (BPA), a model endocrine disruptor, and its major substitute bisphenol S (BPS) were selected. Bovine granulosa cells (primary cultures) and theca explants (ex vivo tissue) were exposed for 24 hr to tritium-labeled BPA, BPS and their respective glucuronides (i.e. their major circulating forms), at concentrations consistent with low-dose exposure scenarios. Mass balance studies were performed, followed by radio-HPLC profiling. The capability of both cell compartments to biotransform BPA and BPS into their respective sulfo-conjugates was demonstrated, with sulfation being the predominant metabolic route. In theca, there was a significantly higher persistence of BPA (compared to BPS) residues over 24 hr. Moreover, only theca explants were able to deconjugate inactive BPA-glucuronide and BPS-glucuronide back into their biologically active aglycone forms. Deconjugation rates were demonstrated to be higher for BPS-G than for BPA-G. These findings raise concerns about the in situ direct release of bisphenols at the level of the ovary and demonstrate the relevance of exploring the biotransformation of bisphenols and their circulating metabolites in different ovarian cells with specific metabolic capabilities. This work also provides essential knowledge for the improved risk assessment of bisphenols.