Evidence for autoregulation and cell signaling pathway regulation from genome-wide binding of the Drosophila retinoblastoma protein.
Evidence for autoregulation and cell signaling pathway regulation from genome-wide binding of the Drosophila retinoblastoma protein.
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DOI：
10.1534/g3.112.004424
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Arnosti DN
中科院分区：
文献类型：
--
作者：
Acharya P;Negre N;Johnston J;Wei Y;White KP;Henry RW;Arnosti DN
视网膜母细胞瘤 (RB) 肿瘤抑制蛋白是一种转录辅助因子，在细胞周期和发育中发挥重要作用。 RB 及其旁系同源物 p107/p130 的物理和功能靶标已主要在培养细胞中进行研究，但该蛋白质家族活性的完整生物学背景可能只有在整个有机体研究中才能揭示。为了确定果蝇 RB 在发育过程中主要对应物的直接靶标，我们对胚胎中的 Rbf1 进行了 ChIP-Seq 分析。蛋白质与启动子的结合是受发育控制的；早期启动子的进入受到全面抑制，而在发育后期，Rbf1被发现与大约2000个基因的启动子近端区域相关。除了保守的细胞周期相关基因之外，一个完全出乎意料的发现是，Rbf1 还靶向胰岛素、Hippo、JAK/STAT、Notch 和其他保守信号通路的许多成分。因此，Rbf1 可能通过调节受体、激酶和下游效应器的表达来直接影响这些重要的生长控制和分化途径的输出。 Rbf1 还被发现针对其自身监管层级的多个级别。生物信息学分析表明，不同类别的基因表现出与 Rbf1 结合区域相关的不同基序群，这表明 Rbf1 调节子内 Rbf1 募集的背景可能有所不同。许多这些靶基因与人类细胞中的 Rbf1 同源物结合，表明 RB 蛋白的保守作用可能是调整生长和发育所必需的互连信号网络的设定点。
The retinoblastoma (RB) tumor suppressor protein is a transcriptional cofactor with essential roles in cell cycle and development. Physical and functional targets of RB and its paralogs p107/p130 have been studied largely in cultured cells, but the full biological context of this family of proteins’ activities will likely be revealed only in whole organismal studies. To identify direct targets of the major Drosophila RB counterpart in a developmental context, we carried out ChIP-Seq analysis of Rbf1 in the embryo. The association of the protein with promoters is developmentally controlled; early promoter access is globally inhibited, whereas later in development Rbf1 is found to associate with promoter-proximal regions of approximately 2000 genes. In addition to conserved cell-cycle–related genes, a wholly unexpected finding was that Rbf1 targets many components of the insulin, Hippo, JAK/STAT, Notch, and other conserved signaling pathways. Rbf1 may thus directly affect output of these essential growth-control and differentiation pathways by regulation of expression of receptors, kinases and downstream effectors. Rbf1 was also found to target multiple levels of its own regulatory hierarchy. Bioinformatic analysis indicates that different classes of genes exhibit distinct constellations of motifs associated with the Rbf1-bound regions, suggesting that the context of Rbf1 recruitment may vary within the Rbf1 regulon. Many of these targeted genes are bound by Rbf1 homologs in human cells, indicating that a conserved role of RB proteins may be to adjust the set point of interlinked signaling networks essential for growth and development.
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影响因子：
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