RESUMEN
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors. This caused an accumulation of differentiation-arrested multipotent progenitors and loss of myeloid and B cells, mimicking the phenotype caused by Mx1-Cre-mediated conditional deletion of the Myc gene in haematopoietic stem cells. This super-enhancer comprises multiple enhancer modules with selective activity that recruits a compendium of transcription factors, including GFI1b, RUNX1 and MYB. Analysis of mice carrying deletions of individual enhancer modules suggests that specific Myc expression levels throughout most of the haematopoietic hierarchy are controlled by the combinatorial and additive activity of individual enhancer modules, which collectively function as a 'blood enhancer cluster' (BENC). We show that BENC is also essential for the maintenance of MLL-AF9-driven leukaemia in mice. Furthermore, a BENC module, which controls Myc expression in mouse haematopoietic stem cells and progenitors, shows increased chromatin accessibility in human acute myeloid leukaemia stem cells compared to blasts. This difference correlates with MYC expression and patient outcome. We propose that clusters of enhancers, such as BENC, form highly combinatorial systems that allow precise control of gene expression across normal cellular hierarchies and which also can be hijacked in malignancies.
Asunto(s)
Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica , Genes myc/genética , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Leucemia/genética , Leucemia/patología , Familia de Multigenes/genética , Animales , Linfocitos B/citología , Diferenciación Celular , Linaje de la Célula/genética , Cromatina/genética , Cromatina/metabolismo , Regulación hacia Abajo , Femenino , Eliminación de Gen , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Células Madre Multipotentes/citología , Células Mieloides/citología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , Eliminación de Secuencia , Análisis de Supervivencia , Factores de Transcripción/metabolismoRESUMEN
In the originally published version of this Letter, ref. 43 was erroneously provided twice. In the 'Estimation of relative cell-type-specific composition of AML samples' section in the Methods, the citation to ref. 43 after the GEO dataset GSE24759 is correct. However, in the 'Mice' section of the Methods, the citation to ref. 43 after 'TAMERE' should have been associated with a new reference1. The original Letter has been corrected online (with the new reference included as ref. 49).
RESUMEN
Target of rapamycin (TOR) functions as a central sensory hub linking a wide range of external stimuli to gene expression. The mechanisms underlying stimulus-specific transcriptional reprogramming by TOR remain elusive. Here, we describe an in silico analysis in Arabidopsis demonstrating that TOR-repressed genes are associated with either bistable or silent chromatin states. Both states regulated by the TOR signaling pathway are associated with a high level of histone H3K27 trimethylation (H3K27me3) deposited by CURLY LEAF in a specific context with LIKE HETEROCHROMATIN PROTEIN1. The combination of the two epigenetic histone modifications H3K4me3 and H3K27me3 implicates a bistable feature that alternates between an 'on' and an 'off' state, allowing rapid transcriptional changes upon external stimuli. The chromatin remodeler SWI2/SNF2 ATPase BRAHMA activates TOR-repressed genes only at bistable chromatin domains to rapidly induce biotic stress responses. Here, we demonstrate both in silico and in vivo that TOR represses transcriptional stress responses through global maintenance of H3K27me3.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Histonas/genética , Histonas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Cromatina/genética , Cromatina/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Ensamble y Desensamble de Cromatina , Regulación de la Expresión Génica de las Plantas , Fosfatidilinositol 3-Quinasas/genéticaRESUMEN
In almost all eukaryotes, RNA interference (RNAi) is a natural defence mechanism against foreign nucleic acids, including transposons and viruses. It is generally triggered by long double stranded RNA molecules (dsRNA, >50bp) that are processed into small interfering RNAs (siRNAs). RNAi can be artificially activated by the expression of RNAi triggers through viruses (virus-induced gene silencing, VIGS) and transgenes. Moreover, for almost 10 years, exogenous RNA application methods are developed as tools to induce RNAi in plants. In this review, exogenous RNA application techniques having the potential to activate RNAi with a focus on RNAi-mediated virus resistance will be discussed. Limitations of exogenous RNA applications, targeting of virus vectors and open questions related to mechanistic details that still require further investigation will be pointed out.
Asunto(s)
Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/virología , Interferencia de ARN , Virus ARN/fisiología , Resistencia a la Enfermedad , Enfermedades de las Plantas/genética , Virus ARN/genética , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunologíaRESUMEN
Plant development is highly interconnected with the metabolic state of tissues and cells. Current research efforts focus on the identification of the links and mechanisms that govern the interplay between metabolic and gene-regulatory networks. Genetically encoded sensors that allow detection of small molecules in vivo and at high spatio-temporal resolution promise to be the tools of choice for quantifying and visualizing the dynamics of metabolite flux in plants. We provide an overview about current approaches to measure signaling molecules, such as hormones, calcium and sugars, as well as for monitoring the metabolic state via energy equivalents and pH. Biosensors show great potential to address questions of plant development but there are also limitations where alternative approaches are needed.