RESUMEN
The underlying mechanism of transcriptional co-repressor ETO2 during early erythropoiesis and hemoglobin switching is unclear. We find that absence of ETO2 in mice interferes with down-regulation of PU.1 and GATA2 in the fetal liver, impeding a key step required for commitment to erythroid maturation. In human ß-globin transgenic Eto2 null mice and in human CD34+ erythroid progenitor cells with reduced ETO2, loss of ETO2 results in ineffective silencing of embryonic/fetal globin gene expression, impeding hemoglobin switching during erythroid differentiation. ETO2 occupancy genome-wide occurs virtually exclusively at LDB1-complex binding sites in enhancers and ETO2 loss leads to increased enhancer activity and expression of target genes. ETO2 recruits the NuRD nucleosome remodeling and deacetylation complex to regulate histone acetylation and nucleosome occupancy in the ß-globin locus control region and γ-globin gene. Loss of ETO2 elevates LDB1, MED1 and Pol II in the locus and facilitates fetal γ-globin/LCR looping and γ-globin transcription. Absence of the ETO2 hydrophobic heptad repeat region impairs ETO2-NuRD interaction and function in antagonizing γ-globin/LCR looping. Our results reveal a pivotal role for ETO2 in erythropoiesis and globin gene switching through its repressive role in the LDB1 complex, affecting the transcription factor and epigenetic environment and ultimately restructuring chromatin organization.
Asunto(s)
Cromatina/metabolismo , Eritropoyesis , Proteínas Represoras/metabolismo , Animales , Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/metabolismo , Células Eritroides , Humanos , Células K562 , Proteínas con Dominio LIM/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Ratones , Ratones Noqueados , Factores de Transcripción/metabolismo , gamma-Globinas/metabolismoRESUMEN
Sex and gender are critical contributors to overall health and disease, and considering both in research informs the development of prevention strategies and treatment interventions for both men and women. The National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop on this topic at the 24th Annual Women's Health Congress, which was held in Crystal City, VA, in April 2016. The workshop featured presentations by NIH intramural and extramural scientists who presented data on a variety of topics including polycystic kidney disease, vaccine protection, depression, drug addiction, and cardiovascular disease. In this publication, we discuss the major points of each presentation and demonstrate the importance of considering sex and gender in biomedical research.
Asunto(s)
Investigación Biomédica , Congresos como Asunto , Disparidades en el Estado de Salud , Salud de la Mujer , Enfermedades Cardiovasculares , Trastorno Depresivo Mayor , Femenino , Humanos , National Institutes of Health (U.S.) , Factores Sexuales , Trastornos Relacionados con Sustancias , Estados UnidosRESUMEN
While women have been well represented in medical school and biomedical doctoral degree programs, they do not comprise half of academic medicine faculty positions. Furthermore, there is a significant paucity of women in academic medicine leadership positions, as evidenced by the fact that only 16% of dean positions at United States Medical schools are filled by women. In this commentary, the authors review the state of women in academic medicine and argue that increased representation of women in the academic workforce will lead to economic gains, increased scientific discovery, and improvements to women's health.
Asunto(s)
Investigación Biomédica , Movilidad Laboral , Médicos Mujeres , Ciencia , Salud de la Mujer , Centros Médicos Académicos , Docentes Médicos , Femenino , Humanos , Liderazgo , Facultades de Medicina , Sexismo/psicología , Recursos HumanosRESUMEN
Uncommitted cells of the early mammalian embryo transition through distinct stages of pluripotency, including establishment of ground state "naïve" pluripotency in the early epiblast, transition to a post-implantation "primed" state, and subsequent lineage commitment of the gastrulating epiblast. Previous transcriptional profiling of in vitro models to recapitulate early to late epiblast transition and differentiation suggest that distinct gene regulatory networks are likely to function in each of these states. While the mechanisms underlying transition between pluripotent states are poorly understood, the forkhead family transcription factor Foxd3 has emerged as a key regulatory factor. Foxd3 is required to maintain pluripotent cells of the murine epiblast and for survival, self-renewal and pluripotency of embryonic stem cells (ESCs). Two recent, simultaneous studies have shed light on how Foxd3 regulates gene expression in early cell fate transitions of progenitor cells. While the two publications shared some common findings, they also presented some conflicting results and suggest different models for the mechanisms underlying Foxd3 function. Here, we discuss the key similarities and differences between the publications, highlight data from the literature relevant to their findings, and hypothesize a potential mechanism of Foxd3 action.
RESUMEN
Women continue to face unique barriers in the biomedical workforce that affect their advancement and retention in this field. The National Institutes of Health (NIH) formed the Working Group on Women in Biomedical Careers to address these issues. Through the efforts of the working group, the NIH funded 14 research grants to identify barriers or to develop and/or test interventions to support women in the biomedical workforce. The grantees that were funded through this endeavor later established the grassroots Research Partnership on Women in Biomedical Careers, and they continue to conduct research and disseminate information on the state of women in academic medicine. This Commentary explores the themes introduced in a collection of articles organized by the research partnership and published in this issue of Academic Medicine. The authors highlight the role that government plays in the advancement of women in academic medicine and highlight the findings put forward in this collection.
Asunto(s)
Investigación Biomédica , Movilidad Laboral , Empleos en Salud/tendencias , Médicos Mujeres/tendencias , Sexismo/tendencias , Femenino , Humanos , National Institutes of Health (U.S.) , Estados Unidos , Recursos HumanosRESUMEN
Although women have reached parity at the training level in the biological sciences and medicine, they are still significantly underrepresented in the professoriate and in mid- and senior-level life science positions. Considerable effort has been devoted by individuals and organizations across science sectors to understanding this disparity and to developing interventions in support of women's career development. The National Institutes of Health (NIH) formed the Office of Research on Women's Health (ORWH) in 1990 with the goals of supporting initiatives to improve women's health and providing opportunities and support for the recruitment, retention, reentry, and sustained advancement of women in biomedical careers. Here, the authors review several accomplishments and flagship activities initiated by the NIH and ORWH in support of women's career development during this time. These include programming to support researchers returning to the workforce after a period away (Research Supplements to Promote Reentry into Biomedical and Behavioral Research Careers), career development awards made through the Building Interdisciplinary Research Careers in Women's Health program, and trans-NIH involvement and activities stemming from the NIH Working Group on Women in Biomedical Careers. These innovative programs have contributed to advancement of women by supporting the professional and personal needs of women in science. The authors discuss the unique opportunities that accompany NIH partnerships with the scientific community, and conclude with a summary of the impact of these programs on women in science.
Asunto(s)
Investigación Biomédica , Fuerza Laboral en Salud/tendencias , National Institutes of Health (U.S.) , Selección de Personal/métodos , Ciencia , Sexismo , Femenino , Humanos , Estados UnidosRESUMEN
BACKGROUND: Sex and gender differences play a significant role in the course and outcome of conditions that affect specific organ systems in the human body. Research on differences in the effects of medical intervention has helped scientists develop a number of sex- and gender-specific guidelines on the treatment and management of these conditions. An online series of courses, "The Science of Sex and Gender in Human Health," developed by the National Institutes of Health Office of Research on Women's Health and the U.S. Food and Drug Administration Office of Women's Health, examines sex and gender differences and their implications. Thus far, three online courses have been generated. The first course offers an overview of the scientific and biological basis for sex- and gender-related differences. The second course is focused on disease-specific sex and gender differences in health and behavior and their implications. Finally, the third course covers the influence of sex and gender on disease manifestation, treatment, and outcome. METHODS: Data were obtained using website analytics and post-course surveys. RESULTS: To date, over 1000 individuals have completed at least one course. Additionally, 600 users have received continuing education credit for completing a course in the series. Finally, the majority of respondents to the online course survey have indicated that the courses considerably enhanced their professional effectiveness. CONCLUSIONS: "The Science of Sex and Gender in Human Health" online courses are freely available sources of information that provide healthcare providers and researchers with the resources to successfully account for sex and gender in their medical practice and research programs.
RESUMEN
Women of color face unique health challenges that differ significantly from those of other women and men of color. To bring these issues to light, the National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop at the 23rd Annual Women's Health Congress, which was held in Washington, DC, in April 2015. The workshop featured presentations by NIH intramural and extramural scientists who provided insight on the disparities of a wide range of conditions, including cancer, cardiovascular disease, the risk of HIV infection, and disability in an aging population. In this study, we highlight the major points of each presentation and the ensuing discussion.