UHRF1 regulates alternative splicing by binding to splicing factors and U snRNAs.
UHRF1 regulates alternative splicing by binding to splicing factors and U snRNAs.
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DOI：
10.1093/hmg/ddab178
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发表时间：
2021-07
影响因子：
3.5
通讯作者：
Peng Xu;Lan Zhang;Yao Xiao;Wei Li;Zhiqiang Hu;Rukui Zhang;Jin Li;Feizhen Wu;Yanping Xi
中科院分区：
文献类型：
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作者：
Peng Xu;Lan Zhang;Yao Xiao;Wei Li;Zhiqiang Hu;Rukui Zhang;Jin Li;Feizhen Wu;Yanping Xi
UHRF1 的既定功能与 DNA 生物过程相融合，细胞周期中 DNA 甲基化维持和 DNA 损伤修复就是例证。然而，UHRF1 对 RNA 代谢的潜在影响在很大程度上尚未被探索。在这里，我们揭示了 UHRF1 作为一种新型的替代 RNA 剪接调节因子。 UHRF1 的蛋白质相互作用组鉴定出多种剪接因子。其中，SF3B3可以直接与UHRF1相互作用并参与UHRF1调控的选择性剪接事件。此外，我们研究了 UHRF1 的 RNA 相互作用组，令人惊讶的是，我们在 UHRF1 相关 RNA 成分中鉴定出了 U snRNA（典型的剪接体成分）。出乎意料的是，我们发现H3R2甲基化状态决定了U snRNA，尤其是U2 snRNA的结合偏好。 U snRNA 参与包含 UHRF1 的复合物及其对特定染色质构型的结合偏好，暗示着一种精心策划的机制在发挥作用。我们的结果提供了资源并查明了UHRF1介导的选择性RNA剪接的分子基础，这将有助于我们更好地了解UHRF1在疾病发展中的生理和病理作用。
The well-established functions of UHRF1 converge to DNA biological processes, as exemplified by DNA methylation maintenance and DNA damage repair during cell cycles. However, the potential effect of UHRF1 on RNA metabolism is largely unexplored. Here, we revealed that UHRF1 serves as a novel alternative RNA splicing regulator. The protein interactome of UHRF1 identified various splicing factors. Among them, SF3B3 could interact with UHRF1 directly and participate in UHRF1-regulated alternative splicing events. Furthermore, we interrogated the RNA interactome of UHRF1, and surprisingly, we identified U snRNAs, the canonical spliceosome component, in the UHRF1-associated RNA components. Unexpectedly, we found H3R2 methylation status determines the binding preference of U snRNA, especially U2 snRNA. The involvement of U snRNAs in UHRF1-containing complex and their binding preference to specific chromatin configuration imply a finely orchestrated mechanism at play. Our results provided the resources and pinpointed the molecular basis of UHRF1-mediated alternative RNA splicing, which will help us better our understanding of the physiological and pathological roles of UHRF1 in disease development.