造血
增强子
生物
干细胞
祖细胞
转录因子
运行x1
细胞生物学
增强子rna
癌症研究
髓样
分子生物学
遗传学
基因
作者
Carsten Bahr,Lisa von Paleske,Veli Vural Uslu,Silvia Remeseiro,Nobuki Takayama,Stanley Ng,Alex Murison,Katja Langenfeld,Massimo Petretich,Roberta Scognamiglio,Petra Zeisberger,Amelie S. Benk,Ido Amit,Peter W. Zandstra,Mathieu Lupien,John E. Dick,Andreas Trumpp,François Spitz
出处
期刊:Nature
[Springer Nature]
日期:2018-01-17
卷期号:553 (7689): 515-520
被引量:248
摘要
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.
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