The Short Isoform of NF-YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry
The Short Isoform of NF-YA Belongs to the Embryonic Stem Cell Transcription Factor Circuitry
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DOI：
10.1002/stem.1232
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发表时间：
2012-11-01
期刊：
影响因子：
5.2
通讯作者：
Mantovani, Roberto
中科院分区：
文献类型：
--
作者：
Dolfini, Diletta;Minuzzo, Mario;Mantovani, Roberto
胚胎干细胞（ESCs）的全能性在转录水平上受到少数转录因子（TFs）的控制，这些转录因子促进干细胞的干性并阻止分化。在ESCs中具有特异性活性的基因的启动子和增强子中，最丰富的DNA元件之一是CCAAT盒子，它被NF-Y识别，NF-Y是一种具有组蛋白样亚基snf - yb / nf - yc和序列特异性NF-YA的三聚体。我们发现，短NF-YA异构体nf - yasis在小鼠ESCs （mESCs）中水平高，分化后下降；显性负突变体直接或间接影响重要干细胞基因的表达。转染TAT-NF-YAs蛋白可刺激细胞生长并补偿细胞培养中白血病抑制因子（LIF）的退出。生物信息学分析发现，NF-Y位点在ESCs的茎tf基因组位点中高度富集。具体来说，30% - 50%的NANOG峰具有NF-Y位点，并且NANOG与DNA结合确实需要NF-Y结合。这些数据表明，NF-Y属于控制mESCs的tf的受限圈，具体来说，NF-YAs是这些细胞中的活性亚型。茎CELLS2012;30:24502459
Totipotency of embryonic stem cells (ESCs) is controlled at the transcriptional level by a handful of transcription factors (TFs) that promote stemness and prevent differentiation. One of the most enriched DNA elements in promoters and enhancers of genes specifically active in ESCs is the CCAAT box, which is recognized by NF-Y, a trimer with histone-like subunitsNF-YB/NF-YCand the sequence-specific NF-YA. We show that the levels of the short NF-YA isoformNF-YAsis high in mouse ESCs (mESCs) and drops after differentiation; a dominant negative mutant affects expression of important stem cells genes, directly and indirectly. Protein transfections of TAT-NF-YAs stimulate growth and compensate for withdrawal of leukemia inhibitory factor (LIF) in cell cultures. Bioinformatic analysis identifies NF-Y sites as highly enriched in genomic loci of stem TFs in ESCs. Specifically, 30%50% of NANOG peaks have NF-Y sites and indeed NF-Y-binding is required for NANOG association to DNA. These data indicate that NF-Y belongs to the restricted circle of TFs that govern mESCs, and, specifically, that NF-YAs is the active isoform in these cells. STEM CELLS2012;30:24502459