miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling.
miR-99a/100~125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling.
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DOI：
10.1101/gad.233791.113
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发表时间：
2014-04-15
影响因子：
10.5
通讯作者：
Klusmann JH
中科院分区：
文献类型：
--
作者：
Emmrich S;Rasche M;Schöning J;Reimer C;Keihani S;Maroz A;Xie Y;Li Z;Schambach A;Reinhardt D;Klusmann JH
miR-99a/100、let-7 和 miR-125b 旁系同源物由两个三反子编码，并在造血干细胞 (HSC) 中高度表达。埃姆里奇等人。证明 miR-99a/100∼125b 三顺反子被转录为多顺反子信息，并在功能上汇聚于 TGFβ 途径的组合块。下调肿瘤抑制基因 APC/APC2 可稳定活性 β-连环蛋白并增强 Wnt 信号传导。这些三顺反子 miRNA 通过切换 Wnt 和 TGFβ 信号传导之间的平衡，促进小鼠和人类 HSC 的持续扩增。尽管 microRNA (miRNA) 对干细胞稳态的调节已得到充分研究，但尚不清楚在有组织的多顺反子内基因组编码的单个 miRNA 如何相互作用以诱导整合表型。 miR-99a/100、let-7 和 miR-125b 旁系同源物由人类 11 号和 21 号染色体上的两个三反子编码。它们在造血干细胞 (HSC) 和急性巨核细胞白血病 (AMKL) 中高度表达，AMKL 是一种预后不良的侵袭性白血病。在这里，我们发现 miR-99a/100∼125b 三顺反子被转录为由同源盒转录因子 HOXA10 反式激活的多顺反子信息。对全局基因表达谱、miRNA靶标预测和通路架构的综合分析表明，miR-99a/100、let-7和miR-125b通过靶向四个受体亚基和两个SMAD信号传导转导器，在转化生长因子β（TGFβ）通路的组合块上功能聚合。此外，肿瘤抑制基因腺瘤性息肉病 (APC)/APC2 的下调可稳定活性 β-连环蛋白并增强 Wnt 信号传导。通过切换 Wnt 和 TGFβ 信号传导之间的平衡，这些三顺反子 miRNA 的协同作用促进了小鼠和人类 HSC 在体外或体内的持续扩增，同时有利于巨核细胞分化。因此，我们的研究解释了控制干细胞稳态的miR-99a/100∼125b三反子的高度系统发育保守性，其失调有助于AMKL的发展。
miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons and are highly expressed in hematopoietic stem cells (HSCs). Emmrich et al. demonstrate that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message and functionally converge at the combinatorial block of the TGFβ pathway. Down-regulating tumor suppressor genes APC/APC2 stabilized active β-catenin and enhanced Wnt signaling. These tricistronic miRNAs promoted sustained expansion of murine and human HSCs by switching the balance between Wnt and TGFβ signaling. Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100∼125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor β (TGFβ) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active β-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFβ signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100∼125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.
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影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
影响因子：
14.9
作者：
Altuvia Y;Landgraf P;Lithwick G;Elefant N;Pfeffer S;Aravin A;Brownstein MJ;Tuschl T;Margalit H
通讯作者：
Margalit H
影响因子：
4.4
作者：
Chan, Wen-Ching;Ho, Meng-Ru;Lin, Wen-Chang
通讯作者：
Lin, Wen-Chang
DOI：
10.1073/pnas.1016611107
发表时间：
2010-12-14
影响因子：
11.1
作者：
Bousquet, Marina;Harris, Marian H.;Lodish, Harvey F.
通讯作者：
Lodish, Harvey F.