Transcriptional repression mediated by repositioning of genes to the nuclear lamina
Transcriptional repression mediated by repositioning of genes to the nuclear lamina
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DOI：
10.1038/nature06727
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发表时间：
2008-03-13
期刊：
影响因子：
64.8
通讯作者：
Singh, H.
中科院分区：
文献类型：
--
作者：
Reddy, K. L.;Zullo, J. M.;Singh, H.
核分室化似乎在调节后生基因中起重要作用（1,2）。尽管对免疫球蛋白和其他基因座的研究表明，在核层层和基因抑制之间存在相关性，但这种分区化的功能后果仍未经过测试（2,3）。我们设计了一种将基因诱导诱导到内部核膜（INM）的方法，并测试了这种重新定位对小鼠成纤维细胞中基因活性的后果。在这里，使用三维DNA-免疫媒体，我们证明了将染色体区域重新定位到核层中，这取决于有丝分裂过程中核膜的分解和改革。此外，绑扎会导致层粘连蛋白和INM蛋白的积累，但不与丁香膜异染色质或核孔复合物相关。将基因募集到INM可能会导致其转录抑制作用。最后，我们使用靶向的腺嘌呤甲基化（DAMID）表明，与我们的模型系统一样，INM和Lamina蛋白接触了核周围的非活性免疫球蛋白基因座。我们建议这些分子相互作用可用于分隔和限制免疫球蛋白基因座对转录和重组因子的可及性。
Nuclear compartmentalization seems to have an important role in regulating metazoan genes(1,2). Although studies on immunoglobulin and other loci have shown a correlation between positioning at the nuclear lamina and gene repression, the functional consequences of this compartmentalization remain untested(2,3). We devised an approach for inducible tethering of genes to the inner nuclear membrane ( INM), and tested the consequences of such repositioning on gene activity in mouse fibroblasts. Here, using three- dimensional DNA- immunoFISH, we demonstrate repositioning of chromosomal regions to the nuclear lamina that is dependent on breakdown and reformation of the nuclear envelope during mitosis. Moreover, tethering leads to the accumulation of lamin and INM proteins, but not to association with pericentro-meric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Finally, we use targeted adenine methylation ( DamID) to show that, as is the case for our model system, inactive immunoglobulin loci at the nuclear periphery are contacted by INM and lamina proteins. We propose that these molecular interactions may be used to compartmentalize and to limit the accessibility of immunoglobulin loci to transcription and recombination factors.