A chromatin code for alternative splicing involving a putative association between CTCF and HP1α proteins.
A chromatin code for alternative splicing involving a putative association between CTCF and HP1α proteins.
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DOI：
10.1186/s12915-015-0141-5
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发表时间：
2015-05-02
期刊：
影响因子：
5.4
通讯作者：
Eyras E
中科院分区：
文献类型：
--
作者：
Agirre E;Bellora N;Alló M;Pagès A;Bertucci P;Kornblihtt AR;Eyras E
选择性剪接主要由剪接因子的活性和RNA聚合酶II（RNAPII）的延伸控制。最近的实验表明，一个新的复杂的剪接调控网络涉及染色质，转录和多种蛋白质因子。特别是，CCCTC结合因子（CTCF），Argonaute蛋白AGO 1，和异染色质蛋白1（HP 1）家族的成员已经涉及与染色质相关的剪接和RNAPII的延伸的调节。这些结果提出了一个问题，这些蛋白质是否可能在染色质水平上调节选择性剪接。使用来自两个细胞系的CTCF、AGO 1、HP 1 α、H3 K27 me 3、H3 K9 me 2、H3 K36 me 3、RNAPII、总H3和5 metC以及选择性剪接阵列的染色质免疫沉淀测序（ChIP-Seq）数据，我们分析了它们与染色质结合的组合密码与两个细胞系MCF 7和MCF 10之间的选择性剪接模式的关系。使用机器学习技术，我们确定了与这两种细胞系之间的剪接调控最显著相关的染色质信号的变化。此外，我们已经建立了一个染色质信号在前mRNA上的图谱，即基于染色质的RNA图谱，它可以解释MCF 7和MCF 10之间的606个（68.55%）调节事件。这种染色质密码涉及HP 1 α、CTCF、AGO 1、RNAPII和受调节外显子周围的组蛋白标记的存在，并且可以区分跳跃和包含的模式。此外，我们发现HP 1 α和CTCF活性在受调节的外显子周围以及HP 1 α的推定DNA结合位点处显著相关。我们的研究结果表明，相当数量的选择性剪接事件可能有一个染色质依赖性的调控涉及的关联HP 1 α和CTCF附近的调控外显子。此外，我们发现了HP 1 α和AGO 1参与染色质相关剪接调控的进一步证据。本文的在线版本（doi：10.1186/s12915-015-0141-5）包含补充材料，可供授权用户使用。
Alternative splicing is primarily controlled by the activity of splicing factors and by the elongation of the RNA polymerase II (RNAPII). Recent experiments have suggested a new complex network of splicing regulation involving chromatin, transcription and multiple protein factors. In particular, the CCCTC-binding factor (CTCF), the Argonaute protein AGO1, and members of the heterochromatin protein 1 (HP1) family have been implicated in the regulation of splicing associated with chromatin and the elongation of RNAPII. These results raise the question of whether these proteins may associate at the chromatin level to modulate alternative splicing. Using chromatin immunoprecipitation sequencing (ChIP-Seq) data for CTCF, AGO1, HP1α, H3K27me3, H3K9me2, H3K36me3, RNAPII, total H3 and 5metC and alternative splicing arrays from two cell lines, we have analyzed the combinatorial code of their binding to chromatin in relation to the alternative splicing patterns between two cell lines, MCF7 and MCF10. Using Machine Learning techniques, we identified the changes in chromatin signals that are most significantly associated with splicing regulation between these two cell lines. Moreover, we have built a map of the chromatin signals on the pre-mRNA, that is, a chromatin-based RNA-map, which can explain 606 (68.55%) of the regulated events between MCF7 and MCF10. This chromatin code involves the presence of HP1α, CTCF, AGO1, RNAPII and histone marks around regulated exons and can differentiate patterns of skipping and inclusion. Additionally, we found a significant association of HP1α and CTCF activities around the regulated exons and a putative DNA binding site for HP1α. Our results show that a considerable number of alternative splicing events could have a chromatin-dependent regulation involving the association of HP1α and CTCF near regulated exons. Additionally, we find further evidence for the involvement of HP1α and AGO1 in chromatin-related splicing regulation. The online version of this article (doi:10.1186/s12915-015-0141-5) contains supplementary material, which is available to authorized users.
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