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首页> 外文期刊>Molecular and Cellular Biology >The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression
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The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression

机译：KAP1 Corepressor的功能是协调KRAB锌指蛋白介导的转录抑制所需的从头HP1划界的异染色质微环境的装配。

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KAP1/TIF1β is proposed to be a universal corepressor protein for the KRAB zinc finger protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormone-responsive KRAB and KAP1 repressor proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1α/β/γ and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequences of the transgene, implying that HP1-directed nuclear compartmentalization is required for transcriptional repression by the KRAB/KAP1 repression complex. The combination of these data suggests that KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps.
机译：KAP1 /TIF1β被认为是转录抑制子的KRAB锌指蛋白（KRAB-zfp）超家族的通用共抑制蛋白。为了表征KAP1和KAP1相互作用蛋白在转录抑制中的作用，我们研究了激素反应性KRAB和KAP1阻遏蛋白对稳定整合的报告基因转基因的调控。在这里，我们证明了通过小干扰RNA（siRNA）耗尽内源性KAP1水平会显着抑制染色质模板的KRAB介导的转录抑制。同样，通过siRNA降低HP1α/β/γ和SETDB1的细胞水平可减弱KRAB-KAP1抑制。我们还发现，直接将KAP1连接到DNA足以抑制整合转基因的转录。这项活动绝对取决于KAP1与HP1的相互作用以及完整的PHD手指和KAP1的溴结构域，表明这些结构域在转录共抑制中协同起作用。野生型KAP1抑制状态的实现包括RNA聚合酶II募集减少，组蛋白H3 K9乙酰化和H3K4甲基化水平降低，组蛋白占有率增加，三甲基组蛋白H3K9，H3K36和组蛋白H4K20和HP1富集沉积在转基因的近端调控序列上。包含HP1结合结构域突变的KAP1蛋白无法诱导与转基因DNA序列相关的组蛋白修饰的任何变化，这意味着KRAB / KAP1阻遏复合体的转录阻抑需要HP1定向的核区室化。这些数据的组合表明，KAP1的功能是协调可动态调节组蛋白修饰和HP1沉积变化的活动，以建立异染色质的从头微环境，这是抑制KRAB-zfps基因转录所必需的。

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