H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells.
H3K4 demethylase KDM5B regulates global dynamics of transcription elongation and alternative splicing in embryonic stem cells.
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DOI：
10.1093/nar/gkx251
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发表时间：
2017-06-20
影响因子：
14.9
通讯作者：
Kidder BL
中科院分区：
文献类型：
--
作者：
He R;Kidder BL
染色质的表观遗传调控在控制胚胎干细胞的自我更新和多能性方面起着关键作用。然而，组蛋白去甲基酶和激活组蛋白修饰如三甲基化组蛋白3赖氨酸4(H3K4me3)在RNA聚合酶II(RNAPII)延长和选择性剪接等转录事件中的作用在很大程度上尚不清楚。在本研究中，我们证明了KDM5B，它去甲基化H3K4me3，在调节RNAPII的占据，转录的起始和延伸，以及ES细胞中的选择性剪接事件中发挥着不可或缺的作用。KDM5B缺失导致RNAPII启动子占有率改变，活性基因和具有广泛H3K4me3结构域的基因的RNAPII起始和延伸率降低。此外，我们的结果表明，由KDM5B缺失介导的H3K4me3从启动子到基因体区域的扩散调节了RNAPII的延伸率和ES细胞中的RNA剪接。我们进一步证明KDM5B在选择性剪接外显子附近富含，而KDM5B的缺失导致选择性剪接外显子区域H3K4甲基化水平的改变，这伴随着这些选择性剪接外显子的差异表达。总之，我们的数据表明KDM5B在调节RNAPII延长和选择性剪接方面具有表观遗传学作用，这可能支持ES细胞中不同的mRNA谱系。
Epigenetic regulation of chromatin plays a critical role in controlling embryonic stem (ES) cell self-renewal and pluripotency. However, the roles of histone demethylases and activating histone modifications such as trimethylated histone 3 lysine 4 (H3K4me3) in transcriptional events such as RNA polymerase II (RNAPII) elongation and alternative splicing are largely unknown. In this study, we show that KDM5B, which demethylates H3K4me3, plays an integral role in regulating RNAPII occupancy, transcriptional initiation and elongation, and alternative splicing events in ES cells. Depletion of KDM5B leads to altered RNAPII promoter occupancy, and decreased RNAPII initiation and elongation rates at active genes and at genes marked with broad H3K4me3 domains. Moreover, our results demonstrate that spreading of H3K4me3 from promoter to gene body regions, which is mediated by depletion of KDM5B, modulates RNAPII elongation rates and RNA splicing in ES cells. We further show that KDM5B is enriched nearby alternatively spliced exons, and depletion of KDM5B leads to altered levels of H3K4 methylation in alternatively spliced exon regions, which is accompanied by differential expression of these alternatively splice exons. Altogether, our data indicate an epigenetic role for KDM5B in regulating RNAPII elongation and alternative splicing, which may support the diverse mRNA repertoire in ES cells.
影响因子：
8.3
作者：
Teoh PL;Sharrocks AD
通讯作者：
Sharrocks AD