RESUMO
The sex chromosomes are enriched with germline genes that are activated during the late stages of spermatogenesis. Due to meiotic sex chromosome inactivation (MSCI), these sex chromosome-linked genes must escape silencing for activation in spermatids, thereby ensuring their functions for male reproduction. RNF8, a DNA damage response protein, and SCML2, a germline-specific Polycomb protein, are two major, known regulators of this process. Here, we show that RNF8 and SCML2 cooperate to regulate ubiquitination during meiosis, an early step to establish active histone modifications for subsequent gene activation. Double mutants of Rnf8 and Scml2 revealed that RNF8-dependent monoubiquitination of histone H2A at Lysine 119 (H2AK119ub) is deubiquitinated by SCML2, demonstrating interplay between RNF8 and SCML2 in ubiquitin regulation. Additionally, we identify distinct functions of RNF8 and SCML2 in the regulation of ubiquitination: SCML2 deubiquitinates RNF8-independent H2AK119ub but does not deubiquitinate RNF8-dependent polyubiquitination. RNF8-dependent polyubiquitination is required for the establishment of H3K27 acetylation, a marker of active enhancers, while persistent H2AK119ub inhibits establishment of H3K27 acetylation. Following the deposition of H3K27 acetylation, H3K4 dimethylation is established as an active mark on poised promoters. Together, we propose a model whereby regulation of ubiquitin leads to the organization of poised enhancers and promoters during meiosis, which induce subsequent gene activation from the otherwise silent sex chromosomes in postmeiotic spermatids.
Assuntos
Histonas/metabolismo , Proteínas do Grupo Polycomb/fisiologia , Cromossomos Sexuais/genética , Ativação Transcricional/genética , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação/genética , Acetilação , Animais , Feminino , Masculino , Meiose/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cromossomos Sexuais/metabolismo , Espermátides/fisiologia , Espermatogênese/genéticaRESUMO
OBJECTIVE: To evaluate the willingness of young adult males to use male hormonal contraception and to determine the most desirable formulation. METHODS: An institutional review board-approved survey measuring the willingness to use MHC was dispersed to two distinct populations: University of Cincinnati postgraduate programs and Cincinnati Health Department clinics. Questions on the survey allowed for the collection of demographic characteristics, as well as the preferred method of MHC, and concerns regarding potential adverse effects. This survey was directed at young adult males; therefore, only male participants who were 18 to 35 years old were included for analysis. Results were reported as frequencies in each group and χ2 analyses were performed to compare groups, with a P < 0.05 considered significant. RESULTS: Of 162 total survey participants, 45% would use MHC, whereas 30.9% were unsure and 23.5% would not use MHC. Overall, the University of Cincinnati survey population was more likely to be interested in using MHC than the Cincinnati Health Department population (P < 0.05). In both populations, most were interested in using the injectable form. Cited concerns deterring participants from using MHC were different between these two populations, with University of Cincinnati participants more frequently expressing concerns about possible failure of the contraceptive method, whereas Cincinnati Health Department participants had concerns about potential adverse effects (P < 0.001). CONCLUSIONS: There is significant interest among young adult males in using various forms of MHC, especially in injectable form. Differences in views of MHC were seen in two distinct male populations. Specifically, males who achieved a higher level of education, were employed, or in a relationship were found to more frequently be willing to use MHC. With further research and funding, MHC may serve as a significant way to decrease unintended pregnancies in the future.
Assuntos
Comportamento Contraceptivo/psicologia , Anticoncepcionais Masculinos/uso terapêutico , Contracepção Hormonal/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Adolescente , Adulto , Humanos , Masculino , Adulto JovemRESUMO
SCCOHT is an aggressive malignancy linked to alterations of SMARCA4. We describe the diagnosis and therapy of a 32 year old who received multi-agent chemotherapy and underwent a second look operation with HIPEC followed by high-dose chemotherapy with stem cell transplant. Supportive care, oncofertility, and genetic counseling are described.
Assuntos
Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Pequenas/genética , DNA Helicases/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/genética , Hipercalcemia/terapia , Quimioterapia Intraperitoneal Hipertérmica , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genéticaRESUMO
Endometriosis currently affects ~5.5 million reproductive-aged women in the U.S. with symptoms such as painful periods (dysmenorrhea), chronic pelvic pain, pain with intercourse (dyspareunia), and infertility. It is defined as the presence of endometrial tissue outside the uterine cavity and is found predominately attached to sites within the peritoneal cavity. Diagnosis for endometriosis is solely made through surgery as no consistent biomarkers for disease diagnosis exist. There is no cure for endometriosis and treatments only target symptoms and not the underlying mechanism(s) of disease. The nature of individual predisposing factors or inherent defects in the endometrium, immune system, and/or peritoneal cavity of women with endometriosis remains unclear. The literature over the last 5 years (2010-2015) has advanced our critical knowledge related to hormones, hormone receptors, immune dysregulation, hormonal treatments, and the transformation of endometriosis to ovarian cancer. In this review, we cover the aforementioned topics with the goal of providing the reader an overview and related references for further study to highlight the progress made in endometriosis research, while concluding with critical areas of endometriosis research that are urgently needed.