HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
HMGA1 reprograms somatic cells into pluripotent stem cells by inducing stem cell transcriptional networks.
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HMGA1通过诱导干细胞转录网络将体细胞重编程为多能干细胞。
DOI：
10.1371/journal.pone.0048533
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Resar LM
中科院分区：
文献类型：
--
作者：
Shah SN;Kerr C;Cope L;Zambidis E;Liu C;Hillion J;Belton A;Huso DL;Resar LM
尽管最近的研究已经确定了人类胚胎干细胞（hESCs）中表达的诱导多能性的基因，但正常干细胞功能的分子基础仍然知之甚少。高迁移率组A1 （HMGA1）基因在hESCs和低分化的干细胞样癌症中高度表达；然而，它在这些环境中的作用一直不清楚。我们发现HMGA1在完全重编程的iPSCs和hESCs中高度表达，在ECCs中表达中等水平，在成纤维细胞中表达低水平。当hESCs被诱导分化时，HMGA1减少，并与其他多能性因子相似。相反，强制表达HMGA1会阻碍hESCs的分化。我们还发现HMGA1与Yamanaka因子（OCT4, SOX2, KLF4, cMYC - OSKM）一起增强体细胞向iPSCs的细胞重编程。与OSKM对照相比，HMGA1增加了iPSC菌落的数量和大小。令人惊讶的是，hmga1衍生的iPSCs在体外有正常分化，在体内有良性畸胎瘤形成。在重编程过程中，HMGA1诱导多能基因的表达，包括SOX2、LIN28和cMYC，而在hESCs中敲低HMGA1会导致这些基因的抑制。染色质免疫沉淀显示HMGA1在体内与这些多能性基因的启动子结合。此外，使用短发夹RNA或显性负结构体干扰HMGA1功能可阻止细胞重编程到多能状态。我们的研究结果首次证明了HMGA1可以促进体细胞向完全多能干细胞的细胞重编程。这些发现确定了HMGA1通过诱导驱动多能性的转录网络作为干细胞状态的关键调节因子的新作用。虽然还需要进一步的研究，但这些HMGA1通路可以用于再生医学或作为低分化、干细胞样癌症的新治疗靶点。
Although recent studies have identified genes expressed in human embryonic stem cells (hESCs) that induce pluripotency, the molecular underpinnings of normal stem cell function remain poorly understood. The high mobility group A1 (HMGA1) gene is highly expressed in hESCs and poorly differentiated, stem-like cancers; however, its role in these settings has been unclear. We show that HMGA1 is highly expressed in fully reprogrammed iPSCs and hESCs, with intermediate levels in ECCs and low levels in fibroblasts. When hESCs are induced to differentiate, HMGA1 decreases and parallels that of other pluripotency factors. Conversely, forced expression of HMGA1 blocks differentiation of hESCs. We also discovered that HMGA1 enhances cellular reprogramming of somatic cells to iPSCs together with the Yamanaka factors (OCT4, SOX2, KLF4, cMYC – OSKM). HMGA1 increases the number and size of iPSC colonies compared to OSKM controls. Surprisingly, there was normal differentiation in vitro and benign teratoma formation in vivo of the HMGA1-derived iPSCs. During the reprogramming process, HMGA1 induces the expression of pluripotency genes, including SOX2, LIN28, and cMYC, while knockdown of HMGA1 in hESCs results in the repression of these genes. Chromatin immunoprecipitation shows that HMGA1 binds to the promoters of these pluripotency genes in vivo. In addition, interfering with HMGA1 function using a short hairpin RNA or a dominant-negative construct blocks cellular reprogramming to a pluripotent state. Our findings demonstrate for the first time that HMGA1 enhances cellular reprogramming from a somatic cell to a fully pluripotent stem cell. These findings identify a novel role for HMGA1 as a key regulator of the stem cell state by inducing transcriptional networks that drive pluripotency. Although further studies are needed, these HMGA1 pathways could be exploited in regenerative medicine or as novel therapeutic targets for poorly differentiated, stem-like cancers.
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影响因子：
8
作者：
Dhar, A;Hu, J;Colburn, NH
通讯作者：
Colburn, NH
DOI：
10.1016/j.pan.2012.05.005
发表时间：
2012-07
期刊：
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]
影响因子：
--
作者：
Hillion J;Smail SS;Di Cello F;Belton A;Shah SN;Huso T;Schuldenfrei A;Nelson DM;Cope L;Campbell N;Karikari C;Aderinto A;Maitra A;Huso DL;Resar LM
通讯作者：
Resar LM
影响因子：
11.2
作者：
Hillion J;Dhara S;Sumter TF;Mukherjee M;Di Cello F;Belton A;Turkson J;Jaganathan S;Cheng L;Ye Z;Jove R;Aplan P;Lin YW;Wertzler K;Reeves R;Elbahlouh O;Kowalski J;Bhattacharya R;Resar LM
通讯作者：
Resar LM
影响因子：
3.4
作者：
Chaerkady, Raghothama;Kerr, Candace L.;Kandasamy, Kumaran;Marimuthu, Arivusudar;Gearhart, John D.;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
DOI：
10.1158/1541-7786.mcr-08-0336
发表时间：
2009-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Hillion J;Wood LJ;Mukherjee M;Bhattacharya R;Di Cello F;Kowalski J;Elbahloul O;Segal J;Poirier J;Rudin CM;Dhara S;Belton A;Joseph B;Zucker S;Resar LM
通讯作者：
Resar LM