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The splicing regulator SLU7 is required to preserve DNMT1 protein stability and DNA methylation
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2021-07-21 , DOI: 10.1093/nar/gkab649
Miriam Recalde 1 , María Gárate-Rascón 1 , María Elizalde 1 , María Azkona 1 , M Ujue Latasa 1, 2 , Marina Bárcena-Varela 1 , Bruno Sangro 2, 3, 4 , Maite G Fernández-Barrena 1, 2, 3 , Matías A Ávila 1, 2, 3 , María Arechederra 1, 2 , Carmen Berasain 1, 2, 3
Affiliation  

Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.

中文翻译:

剪接调节剂 SLU7 是保持 DNMT1 蛋白稳定性和 DNA 甲基化所必需的

基因表达通过表观遗传调节剂、转录和剪接因子以及翻译后修饰剂的紧密协调和相互关联的活动进行精细和动态控制。我们最近确定了剪接因子 SLU7 对于维持肝细胞身份和基因组完整性以及通过转录和剪接机制确保细胞分裂至关重要。现在我们发现了 SLU7 在表观遗传水平上控制基因表达的新功能。我们表明 SLU7 是确保 DNMT1 蛋白稳定性和正确 DNA 甲基化所必需的。我们证明 SLU7 是参与 DNA 甲基化维持的蛋白质复合物的染色体的一部分,它与 DNMT1 相互作用并控制其完整性,它的衔接蛋白 UHRF1 和染色质水平的组蛋白甲基转移酶 G9a。从机制上讲,我们发现 SLU7 通过促进其与 HDAC1 和去泛素酶 USP7 的相互作用来确保 DNMT1 的稳定性,从而防止其乙酰化和降解。重要的是,我们证明了这种 DNMT1 对 SLU7 的依赖性发生在一大组不同来源的增殖细胞系和肝脏增殖的体内模型中。总体而言,我们的结果揭示了 SLU7 在 DNA 甲基化中的一种新颖且非冗余的作用,并将 SLU7 呈现为基因表达的整体调节剂。我们证明了这种 DNMT1 对 SLU7 的依赖性发生在一大组不同来源的增殖细胞系和肝脏增殖的体内模型中。总体而言,我们的结果揭示了 SLU7 在 DNA 甲基化中的一种新颖且非冗余的作用,并将 SLU7 呈现为基因表达的整体调节剂。我们证明了这种 DNMT1 对 SLU7 的依赖性发生在一大组不同来源的增殖细胞系和肝脏增殖的体内模型中。总体而言,我们的结果揭示了 SLU7 在 DNA 甲基化中的一种新颖且非冗余的作用,并将 SLU7 呈现为基因表达的整体调节剂。
更新日期:2021-07-21
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