RESUMEN
The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , ARN Largo no Codificante/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Línea Celular Tumoral , Regulación Leucémica de la Expresión Génica , Humanos , Activación TranscripcionalRESUMEN
E-cadherin is a calcium-dependent cell-cell adhesion molecule extensively studied for its involvement in tissue formation, epithelial cell behavior, and suppression of cancer. However, E-cadherin expression in the hematopoietic system has not been fully elucidated. Combining single-cell RNA-sequencing analyses and immunophenotyping, we revealed that progenitors expressing high levels of E-cadherin and contained within the granulocyte-monocyte progenitors (GMPs) fraction have an enriched capacity to differentiate into basophils and mast cells. We detected E-cadherin expression on committed progenitors before the expression of other reported markers of these lineages. We named such progenitors pro-BMPs (pro-basophil and mast cell progenitors). Using RNA sequencing, we observed transcriptional priming of pro-BMPs to the basophil and mast cell lineages. We also showed that GATA-2 directly regulates E-cadherin expression in the basophil and mast cell lineages, thus providing a mechanistic connection between the expression of this cell surface marker and the basophil and mast cell fate specification.
Asunto(s)
Cadherinas/genética , Factor de Transcripción GATA2/metabolismo , Células Madre Hematopoyéticas/fisiología , Animales , Basófilos/fisiología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Mastocitos/fisiología , Ratones , Cultivo Primario de Células , RNA-Seq , Análisis de la Célula IndividualRESUMEN
RESUMO Esta pesquisa busca entender o processo de participação na organização dos Jogos Goianos da Saúde Mental. A finalidade é contribuir com a reflexão sobre as possibilidades e limites de construção de redes de cuidado em saúde mental. Trata-se de pesquisa com análise documental, de abordagem descritiva e qualitativa, que seguiu procedimentos de análise de conteúdo. Identificaram-se duas categorias empíricas, a saber: da participação presencial à construção de rede; e decisões que impactaram a participação dos usuários. Advoga-se aqui uma participação profunda que mobiliza sonhos coletivos que as práticas manicomiais não conseguem colocar em uma camisa de força.
ABSTRACT This research project seeks to understand the process of participation in the organization of the Mental Health Games of Goiás. It aims to contribute to the reflection on the possibilities and limits of building mental health care networks. This is a documentary analysis research project, with descriptive and qualitative approach, which followed content analysis procedures. Two empirical categories were identified, namely: from face-to-face participation to network construction; and decisions that impacted the participation of users. A profound participation is advocated, which mobilizes collective dreams that asylum practices cannot put on a straitjacket.
RESUMEN Esta investigación busca comprender el proceso de participación en la organización de los Juegos Goianos de Salud Mental. El objetivo es contribuir a la reflexión sobre las posibilidades y los límites de la construcción de redes de atención de salud mental. Se trata de una investigación con análisis documental, enfoque descriptivo y cualitativo, que siguió los procedimientos de análisis de contenido. Se identificaron dos categorías empíricas, a saber: desde la participación cara a cara hasta la construcción de redes; y decisiones que afectaron la participación de los usuarios. Aquí se aboga por una participación profunda que movilice sueños colectivos que las prácticas manicomiales no pueden poner en una camisa de fuerza.