Shanghai Public Health Clinical Centre and Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 201508, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
Hum Mol Genet. 2021 Nov 1;30(22):2110-2122. doi: 10.1093/hmg/ddab178.
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 components, in the purified UHRF1 complex. Unexpectedly, we found H3R2 methylation status determines the binding preference of U snRNAs, especially U2 snRNAs. 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.
UHRF1 的诸多功能已被广泛证实与 DNA 生物学过程有关，例如在细胞周期中维持 DNA 甲基化和修复 DNA 损伤。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 是一种新型的可变剪接调控因子。UHRF1 的蛋白互作组鉴定出了各种剪接因子。其中，SF3B3 可以与 UHRF1 直接相互作用，并参与 UHRF1 调控的可变剪接事件。此外，我们还研究了 UHRF1 的 RNA 互作组，令人惊讶的是，我们在纯化的 UHRF1 复合物中鉴定到了 U 小核仁 RNA（U snRNA），这是经典剪接体的组成部分。出乎意料的是，我们发现 H3R2 甲基化状态决定了 U snRNA 的结合偏好性，尤其是 U2 snRNA。U snRNA 参与 UHRF1 包含的复合物及其对特定染色质构象的结合偏好性暗示了一种精细的调控机制在起作用。我们的研究结果提供了资源并指出了 UHRF1 介导的可变 RNA 剪接的分子基础，这将有助于我们更好地理解 UHRF1 在疾病发展过程中生理和病理作用。
