SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia.
SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia.
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SON通过抑制急性巨核细胞白血病中的RUNX1和巨核细胞基因表达程序来抑制巨核细胞分化。
DOI：
10.1038/s41417-020-00262-9
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发表时间：
2021-09
影响因子：
6.4
通讯作者：
Ahn EE
中科院分区：
文献类型：
--
作者：
Vukadin L;Kim JH;Park EY;Stone JK;Ungerleider N;Baddoo MC;Kong HK;Richard A;Tran J;Giannini H;Flemington EK;Lim SS;Ahn EE
唐氏综合征患者急性巨核母细胞白血病（AMKL）的高发病率表明，21号染色体基因在AMKL的发展中起关键作用，但个体基因的功能贡献尚不清楚。在这里，我们报道了SON，一个21号染色体编码的DNA和rna结合蛋白，通过抑制RUNX1和巨核细胞基因表达程序来抑制巨核细胞分化。随着巨核细胞祖细胞的分化，SON表达急剧降低，成熟巨核细胞表达水平最低。相反，AMKL细胞表达异常高水平的SON， SON的敲低诱导AMKL细胞系的巨核细胞分化。全基因组转录组分析显示，SON基因敲低可以激活巨核细胞前基因的表达，同时降低红系基因的表达。从机制上讲，SON通过直接结合RUNX1位点的近端启动子和两个增强子区域（已知的+23 kb增强子和新的+139 kb增强子）来抑制RUNX1的表达，从而抑制H3K4甲基化。此外，SON还抑制巨核细胞晚期基因表达所需的AP-1复合物亚基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，暗示SON过表达在AMKL发育过程中分化受损。
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.
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影响因子：
--
作者：
Fan J;Wang Y;Shen Y;Liu Q;Gao R;Qiu Y;Wang C;Zhang L
通讯作者：
Zhang L
影响因子：
16
作者：
Kim JH;Baddoo MC;Park EY;Stone JK;Park H;Butler TW;Huang G;Yan X;Pauli-Behn F;Myers RM;Tan M;Flemington EK;Lim ST;Ahn EY
通讯作者：
Ahn EY
DOI：
10.1126/science.1251033
发表时间：
2014-09-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kostadima M;Martens JHA;Canu G;Garcia SP;Turro E;Downes K;Macaulay IC;Bielczyk-Maczynska E;Coe S;Farrow S;Poudel P;Burden F;Jansen SBG;Astle WJ;Attwood A;Bariana T;de Bono B;Breschi A;Chambers JC;Consortium B;Choudry FA;Clarke L;Coupland P;van der Ent M;Erber WN;Jansen JH;Favier R;Fenech ME;Foad N;Freson K;van Geet C;Gomez K;Guigo R;Hampshire D;Kelly AM;Kerstens HHD;Kooner JS;Laffan M;Lentaigne C;Labalette C;Martin T;Meacham S;Mumford A;Nürnberg S;Palumbo E;van der Reijden BA;Richardson D;Sammut SJ;Slodkowicz G;Tamuri AU;Vasquez L;Voss K;Watt S;Westbury S;Flicek P;Loos R;Goldman N;Bertone P;Read RJ;Richardson S;Cvejic A;Soranzo N;Ouwehand WH;Stunnenberg HG;Frontini M;Rendon A
通讯作者：
Rendon A
影响因子：
20.3
作者：
Geue，Sascha;Aurbach，Katja;Borst，Oliver
通讯作者：
Borst，Oliver
DOI：
10.1073/pnas.93.5.1935
发表时间：
1996-03-05
影响因子：
11.1
作者：
Ghozi, MC;Bernstein, Y;Groner, Y
通讯作者：
Groner, Y