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SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia
Cancer Gene Therapy ( IF 4.8 ) Pub Date : 2020-11-27 , DOI: 10.1038/s41417-020-00262-9
Lana Vukadin 1, 2, 3 , Jung-Hyun Kim 2 , Eun Young Park 2 , Joshua K Stone 2 , Nathan Ungerleider 4 , Melody C Baddoo 4 , Hyun Kyung Kong 2 , Alexander Richard 2, 3 , Johnny Tran 2, 3 , Hannah Giannini 2, 3 , Erik K Flemington 4 , Ssang-Taek Steve Lim 3 , Eun-Young Erin Ahn 1, 5
Affiliation  

A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB, and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.



中文翻译:

SON 通过抑制 RUNX1 和急性巨核细胞白血病中的巨核细胞基因表达程序抑制巨核细胞分化

唐氏综合症患者急性巨核细胞白血病 (AMKL) 的高发病率意味着 21 号染色体基因在 AMKL 发展中起着关键作用,但个别基因的功能贡献仍然难以捉摸。在这里,我们报道了 SON,一种由 21 号染色体编码的 DNA 和 RNA 结合蛋白,通过抑制RUNX1来抑制巨核细胞分化和巨核细胞基因表达程序。随着巨核细胞祖细胞的分化,SON 表达急剧减少,成熟的巨核细胞水平最低。相反,AMKL 细胞表达异常高水平的 SON,并且 SON 的敲低诱导 AMKL 细胞系中巨核细胞分化的开始。全基因组转录组分析表明,SON 敲低会开启促巨核细胞基因的表达,同时降低红系基因的表达。从机制上讲,SON 通过直接结合 RUNX1 的近端启动子和两个增强子区域(已知的 +23 kb 增强子和新型 +139 kb 增强子)来抑制 RUNX1 的表达位点抑制 H3K4 甲基化。此外,SON 抑制晚期巨核细胞基因表达所需的 AP-1 复合亚基 JUN、JUNB 和 FOSB 的表达。我们的研究结果将 SON 定义为 RUNX1 和巨核细胞分化的负调节因子,表明 SON 过表达在 AMKL 发育过程中分化受损。

更新日期:2020-11-27
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