RESUMO
PURPOSE: The field of genetics and genomics continues to expand at an unprecedented pace. As scientific knowledge is translated to clinical practice, genomic information is routinely being used in preventive, diagnostic, and therapeutic decision-making across a variety of clinical practice areas. As adoption of genomic medicine further evolves, health professionals will be required to stay abreast of new genetic discoveries and technologies and implementation of these advances within their scope of practice will be indicated. METHODS: The Association of Professors of Human and Medical Genetics previously developed medical school genetics core competencies, last updated in 2013. The competencies were reviewed and updated through a structured approach incorporating a modified Delphi method. RESULTS: The updated Association of Professors of Human and Medical Genetics core competencies are presented. Current revisions include competencies that are concise, specific, and assessable. In addition, they incorporate recent advances in clinical practice and promote equity and inclusion in clinical care. CONCLUSION: The 2022 competencies will serve as a guide for medical school leadership and educators involved in curriculum development, implementation, and assessment. Use of these competencies across the undergraduate medical curricula will foster knowledge, skills, and behaviors required in medical practice across a wide range of specialties.
Assuntos
Educação de Graduação em Medicina , Genética Médica , Competência Clínica , Consenso , Currículo , Genética Médica/educação , Genômica/educação , HumanosRESUMO
The expansion of repressive epigenetic marks has been implicated in heterochromatin formation during embryonic development, but the general applicability of this mechanism is unclear. Here we show that nuclear rearrangement of repressive histone marks H3K9me3 and H3K27me3 into nonoverlapping structural layers characterizes senescence-associated heterochromatic foci (SAHF) formation in human fibroblasts. However, the global landscape of these repressive marks remains unchanged upon SAHF formation, suggesting that in somatic cells, heterochromatin can be formed through the spatial repositioning of pre-existing repressively marked histones. This model is reinforced by the correlation of presenescent replication timing with both the subsequent layered structure of SAHFs and the global landscape of the repressive marks, allowing us to integrate microscopic and genomic information. Furthermore, modulation of SAHF structure does not affect the occupancy of these repressive marks, nor vice versa. These experiments reveal that high-order heterochromatin formation and epigenetic remodeling of the genome can be discrete events.
Assuntos
Cromatina/química , Heterocromatina/química , Histonas/metabolismo , Bromodesoxiuridina/farmacologia , Senescência Celular , Cromossomos/ultraestrutura , Epigênese Genética , Fibroblastos/citologia , Regulação da Expressão Gênica no Desenvolvimento , Inativação Gênica , Genoma , Estudo de Associação Genômica Ampla , Histonas/química , Humanos , Citometria de Varredura a Laser/métodos , Microscopia de Fluorescência/métodosRESUMO
Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16(INK4a) tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.
Assuntos
Núcleo Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Senescência Celular/genética , Proteínas HMGA/metabolismo , Heterocromatina/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Linhagem Celular , Núcleo Celular/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Células Cultivadas , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Proteínas HMGA/genética , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Heterocromatina/genética , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Ativação Transcricional/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Cellular senescence is an extremely stable form of cell cycle arrest that limits the proliferation of damaged cells and may act as a natural barrier to cancer progression. In this study, we describe a distinct heterochromatic structure that accumulates in senescent human fibroblasts, which we designated senescence-associated heterochromatic foci (SAHF). SAHF formation coincides with the recruitment of heterochromatin proteins and the retinoblastoma (Rb) tumor suppressor to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Notably, both SAHF formation and the silencing of E2F target genes depend on the integrity of the Rb pathway and do not occur in reversibly arrested cells. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor.