Transcription factor redundancy and tissue-specific regulation: evidence from functional and physical network connectivity.
Transcription factor redundancy and tissue-specific regulation: evidence from functional and physical network connectivity.
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DOI：
10.1101/gr.133306.111
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发表时间：
2012-10
期刊：
影响因子：
7
通讯作者：
Wold BJ
中科院分区：
文献类型：
--
作者：
Kuntz SG;Williams BA;Sternberg PW;Wold BJ
秀丽隐杆线虫体壁肌 (BWM) 分化的两个主要转录调节因子 hlh-1 和 unc-120 在肌肉中表达，已知它们可以结合和调节几个经过充分研究的肌肉特异性基因。同时突变这两个因素会极大地抑制收缩性 BWM 的形成。这些观察结果与一个简单的网络模型一致，在该模型中，肌肉调节因子通过选择性地结合肌肉特异性靶标附近以激活它们来驱动组织特异性转录。我们通过测量每个因素的功能调节目标的数量、身份和组织特异性来测试该模型。一些联合监管目标 (218) 是 BWM 特异性的，并且针对附近的 HLH-1 结合进行了丰富。然而，与简单模型相反，受一种或两种肌肉因子调节的大多数基因也在非 BWM 组织中显着表达。我们还绘制了 HLH-1 的全局因子占据图，并创建了识别 hlh-1 协作转录因子的遗传相互作用图谱。尽管 hlh-1 的 BWM 特异性正调控靶点之间的结合富集，但 HLH-1 结合并不能预测整体的近期调控作用。我们得出的结论是，这些组织特异性因子对肌肉组织转录输出的贡献比之前想象的要广泛得多，这为 HLH-1 的广泛存在提供了部分解释。我们还发现了 BWM 特异性 hlh-1 网络和 hlh-8/twist 非横纹肌网络之间的新型调节联系。最后，我们的结果提出了合成致死性的分子基础，其中 hlh-1 和 unc-120 突变表型通过基本靶基因的联合加性调节相互缓冲，并通过新鉴定的 hlh-1 相互作用因子暗示额外的缓冲。
Two major transcriptional regulators of Caenorhabditis elegans bodywall muscle (BWM) differentiation, hlh-1 and unc-120, are expressed in muscle where they are known to bind and regulate several well-studied muscle-specific genes. Simultaneously mutating both factors profoundly inhibits formation of contractile BWM. These observations were consistent with a simple network model in which the muscle regulatory factors drive tissue-specific transcription by binding selectively near muscle-specific targets to activate them. We tested this model by measuring the number, identity, and tissue-specificity of functional regulatory targets for each factor. Some joint regulatory targets (218) are BWM-specific and enriched for nearby HLH-1 binding. However, contrary to the simple model, the majority of genes regulated by one or both muscle factors are also expressed significantly in non-BWM tissues. We also mapped global factor occupancy by HLH-1, and created a genetic interaction map that identifies hlh-1 collaborating transcription factors. HLH-1 binding did not predict proximate regulatory action overall, despite enrichment for binding among BWM-specific positive regulatory targets of hlh-1. We conclude that these tissue-specific factors contribute much more broadly to the transcriptional output of muscle tissue than previously thought, offering a partial explanation for widespread HLH-1 occupancy. We also identify a novel regulatory connection between the BWM-specific hlh-1 network and the hlh-8/twist nonstriated muscle network. Finally, our results suggest a molecular basis for synthetic lethality in which hlh-1 and unc-120 mutant phenotypes are mutually buffered by joint additive regulation of essential target genes, with additional buffering suggested via newly identified hlh-1 interacting factors.
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DOI：
10.1083/jcb.101.4.1532
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Francis GR;Waterston RH
通讯作者：
Waterston RH
DOI：
10.1073/pnas.0404192101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Dilworth, FJ;Seaver, KJ;Tapscott, SJ
通讯作者：
Tapscott, SJ
影响因子：
4.6
作者：
Amin, Nirav M.;Hu, Kejin;Liu, Jun
通讯作者：
Liu, Jun
影响因子：
56.9
作者：
BLACKWELL, TK;BOWERMAN, B;WEINTRAUB, H
通讯作者：
WEINTRAUB, H
影响因子：
7
作者：
GuhaThakurta, D;Schriefer, LA;Stormo, GD
通讯作者：
Stormo, GD