BRD3 and BRD4 BET bromodomain proteins differentially regulate skeletal myogenesis

Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4

BRD3 and BRD4 BET bromodomain proteins differentially regulate skeletal myogenesis

Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts. All three BET proteins BRD2, BRD3 and BRD4 exhibited distinct and dynamic patterns of protein expression over the course of differentiation without concomitant changes in mRNA levels, suggesting that BET proteins are regulated at the post-transcriptional level. Specific BET protein knockdown by RNA interference revealed that BRD4 was required for myogenic differentiation, whereas BRD3 down-regulation resulted in enhanced myogenic differentiation. ChIP experiments revealed a preferential binding of BRD4 to the Myog promoter during C2C12 myoblast differentiation, co-incident with increased levels of H3K27 acetylation. These results have identified an essential role for BET proteins in the regulation of skeletal myogenesis, and assign distinct functions to BRD3 and BRD4

Evento com aparente risco de morte: uma revisão Evento con aparente riesgo de muerte (alte): una revisión Apparent life-threatening event: a review

OBJETIVO: Realizar uma revisão crítica reunindo informações disponíveis a respeito dos eventos com aparente risco de morte. FONTES DE DADOS: Revisão bibliográfica dos artigos (em português, inglês e espanhol) obtidos dos bancos de dados eletrônicos Medline, Lilacs e SciELO, utilizando as palavras-chave: eventos com aparente risco de morte, evento com aparente risco de vida infantil, lactente, apneia, monitorização e cianose. SÍNTESE DOS DADOS: Os eventos com aparente risco de mortesão súbitos e caracterizados por uma combinação de apneia, alteração na coloração da pele e tônus muscular, com inúmeras causas subjacentes. Sua incidência verdadeira é desconhecida e a faixa etária mais acometida é de 11 a 12 semanas. Não há correlação entre o evento com aparente risco de morte e a síndrome da morte súbita do lactente, embora já tenham sido consideradas manifestações da mesma doença. Muitas vezes, o lactente tem aparência saudável ao ser avaliado pelo pediatra após apresentar eventos com aparente risco de morte, porém, isso não afasta a possibilidade de existir uma doença grave associada ao evento, que deve ser investigada e tratada. Quando não são encontradas as causas, o evento é idiopático, geralmente com boa evolução. CONCLUSÕES: É necessário investigar os lactentes levados ao pronto-socorro após apresentarem eventos com aparente risco de morte, devido ao risco de sequelas e mortalidade. Não há uma padronização das condutas a serem realizadas diante de um lactente com aparência saudável que tenha evento com aparente risco de morte, mas recomenda-se que o paciente seja internado e a causa do evento, investigada. A observação e o monitoramento em ambiente hospitalar devem ocorrer no mínimo 24 horas após o evento.<br>OBJETIVO: Realizar una revisión crítica, reuniendo las informaciones disponibles respecto a los Eventos con Aparente Riesgo de Muerte (ALTE - Apparent life-threatening event). FUENTES DE DATOS: Revisión bibliográfica de los artículos (en portugués, inglés y español) obtenidos de las bases de datos electrónicas MEDLINE, LILACS y SCIELO, utilizándose las palabras clave ALTE, evento con aparente riesgo de vida infantil, lactante, apnea, monitorización y cianosis. SÍNTESIS DE LOS DATOS: Los ALTE (apparent life-threatening event) son eventos súbitos y caracterizados por una combinación de apnea, alteración en la coloración de la piel y tono muscular, con innúmeras causas subyacentes. Su incidencia verdadera es desconocida y la franja de edad más acometida es de 11 a 12 semanas. No hay correlación entre ALTE y SIDS (Síndrome de la Muerte Súbita del Lactante), aunque ya hayan sido consideradas manifestaciones de la misma enfermedad. Muchas veces, el lactante tiene apariencia sana al ser evaluado por el pediatra después de presentar ALTE, pero eso no aleja la posibilidad de que exista una enfermedad grave asociada al evento, la cual se debe investigar y tratar. Cuando no se encuentran causas, el evento es idiopático, generalmente con buena evolución. CONCLUSIONES: Es necesario investigar los lactantes llevados a la emergencia después de presentar ALTE, por riesgo de secuelas y de mortalidad. No hay una estandarización de las conductas a tomar frente a un lactante con apariencia sana que presentó ALTE, pero se recomienda que se interne el paciente y se investigue la causa del evento. La observación y monitoración en ambiente hospitalaria debe ocurrir por un mínimo de 24 horas después del evento.<br>OBJECTIVE: To perform a critical review by gathering all the available information about apparent life-threatening events. DATA SOURCES: Bibliographic review of the articles published in Portuguese, English and Spanish from the electronic databases Medline, Lilacs and SciELO, using the key-words: apparent life-threatening events, apparent life-threatening event, infant, apnea, monitoring, and cyanosis. DATA SYNTHESIS: Apparent life-threatening events define sudden events with, a combination of apnea, color change, and marked change in the muscle tone, that have various underlying causes. The real incidence remains unknown, and it affects infants from 11 to 12 weeks of age. There is no association between apparent life-threatening events and sudden infant death syndrome. There are many possible causes for the events, and they must be investigated even in apparently healthy infants, because the presence of a severe underlying disease associated with the event is possible. If the cause of the apparent life-threatening events is found, it must be treated properly. If there is no explainable cause, the event is considered idiopathic and generally has a benign course. CONCLUSIONS: It is necessary to investigate all the infants taken to the pediatric emergency unit after experiencing an apparent life-threatening event, since there is the risk of morbidity caused by an underlying disease or the event itself, as well as subsequent mortality. Consensus guidelines about the investigation in apparently healthy infants who experienced apparent life-threatening events are not available. Most authors recommend that careful observation and hospital monitoring should be performed for at least for 24 hours after the event

The Glial Differentiation Factor Nuclear Factor One B (Nfib) Induces Differentiation and Inhibits Growth of Glioblastoma.

International audienceThe molecule CD90 is a N-glycosylated, glycophosphatidylinositol anchored cell surface protein, originally described on thymocytes. CD90 has been considered as a surrogate marker for a variety of stem cells and has recently been reported on glioblastoma stem cells. CD90 is also expressed on T lymphocytes, endothelial cells, fibroblasts and neurons. The function of CD90 is not fully elucidated. CD90 has been involved in cell-cell and cell-matrix interactions, in neurite outgrowth, T cell activation and apoptosis. In this study, we confirmed the expression of CD90 on human glioblastoma stem-like cells from serum-free neurosphere cultures. We also observed RNA and protein CD90 expression on primary cell lines from FSC-containing culture (adherent cell lines) and on freshly prepared glioblastoma specimen. In order to study the function of CD90 on glioblastoma cells, we used a silencing strategy to decrease the expression of CD90 on the immortalized U251 cell line. We then compared the viability, the tumor growth and the migration property of the wild-type CD90+ U251 cells and CD90 down-regulated U251 clones. The decrease of CD90 expression did not affect the viability and the tumor growth of U251 cells. In contrast, down-regulation of CD90 mediated the decreased ability of tumor cell migration using both scratch wound healing and boyden chamber migration assays. Experiments are currently on going to test the effect of CD90 expression on tumorigenicity in mice models. In total, this study might lead to better understand the role of CD90 on the pathology in particular in term of tumor migration/invasion of human glioblastoma