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无翅蛋白-I通过将小泛素样修饰蛋白异肽酶SENP3招募到不同基因来调控细胞命运。

Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct genes.

作者信息

Nayak Arnab, Reck Anja, Morsczeck Christian, Müller Stefan

机构信息

Institute of Biochemistry II, Goethe University Medical School, University Hospital Building 75, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Department of Oral and Maxillofacial Surgery, University of Regensburg, 93042 Regensburg, Germany.

出版信息

Epigenetics Chromatin. 2017 Mar 23;10:15. doi: 10.1186/s13072-017-0122-8. eCollection 2017.

DOI:10.1186/s13072-017-0122-8
PMID:28344658
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5364561/
Abstract

BACKGROUND

Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct genes, including the osteogenic master regulator . A comprehensive mechanism that regulates SENP3 transcriptional function was not understood.

RESULTS

Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on the gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells.

CONCLUSION

Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination.

摘要

背景

尽管最近有关于泛素相关小泛素样修饰物在细胞命运决定中作用的研究，但我们对这些过程精确分子机制的理解仍然有限。此前，我们已证实小泛素样修饰物蛋白酶 SENP3 在包括成骨主调节因子在内的不同基因上调节 MLL1/2 组蛋白甲基转移酶复合物的染色质组装。但尚未了解调节 SENP3 转录功能的全面机制。

结果

在此，我们鉴定出肌动蛋白重塑蛋白凝溶胶蛋白家族成员无翅 I 同源物（FLII）是 SENP3 的新型调节因子。我们证明 FLII 与 SENP3 和 MLL1/2 复合物相关联。我们进一步表明，FLII 决定 SENP3 在该基因上的募集以及 MLL1/2 复合物的组装。因此，FLII 对于该基因位点的 H3K4 甲基化和活性 RNA 聚合酶 II 的正确加载不可或缺。最重要的是，FLII 介导的 SENP3 调节控制人间充质干细胞的成骨分化。

结论

总之，这些数据揭示了 FLII 与小泛素样修饰系统之间至关重要的功能联系，该联系集中于表观遗传调控和细胞命运决定。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/195b55f8e09b/13072_2017_122_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/2ded6808c2a7/13072_2017_122_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a9b5c19693b2/13072_2017_122_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a49f73754029/13072_2017_122_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a30977975005/13072_2017_122_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/195b55f8e09b/13072_2017_122_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/2ded6808c2a7/13072_2017_122_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a9b5c19693b2/13072_2017_122_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a49f73754029/13072_2017_122_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/a30977975005/13072_2017_122_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d065/5364561/195b55f8e09b/13072_2017_122_Fig5_HTML.jpg

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