Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis
Tissue-Specific Gene Repositioning by Muscle Nuclear Membrane Proteins Enhances Repression of Critical Developmental Genes during Myogenesis
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DOI：
10.1016/j.molcel.2016.04.035
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发表时间：
2016-06-16
期刊：
影响因子：
16
通讯作者：
Schirmer, Eric C.
中科院分区：
文献类型：
--
作者：
Robson, Michael I.;de las Heras, Jose I.;Schirmer, Eric C.
在分化过程中基因重新定位到核周边是否为基因表达增加了另一层调控仍然存在争议。在这里，我们通过操纵基因的位置，通过靶向核膜跨膜蛋白（NET），指导他们的正常重新定位在肌发生解决这个问题。结合转录组学与高分辨率DamID映射的核膜基因组接触，我们表明，三个肌肉特异性NET，NET 39，Tmem 38 A，和WFS 1，直接特定的肌源性基因的核周边，以促进其镇压。将NET 39片段重新靶向到核仁相应地重新定位靶基因，表明直接拴系机制。能够独立于分化中的其他变化来操纵基因位置，这表明重新定位贡献了肌生成中基因正常抑制的1/3至2/3。总之，这些NET影响了肌发生过程中37%的基因表达变化，它们的联合敲除几乎完全阻断了肌管的形成。这明确地表明，NET指导的基因重新定位是发育基因调控的关键。
Whether gene repositioning to the nuclear periphery during differentiation adds another layer of regulation to gene expression remains controversial. Here, we resolve this by manipulating gene positions through targeting the nuclear envelope transmembrane proteins (NETs) that direct their normal repositioning during myogenesis. Combining transcriptomics with high-resolution DamID mapping of nuclear envelope-genome contacts, we show that three muscle-specific NETs, NET39, Tmem38A, and WFS1, direct specific myogenic genes to the nuclear periphery to facilitate their repression. Retargeting a NET39 fragment to nucleoli correspondingly repositioned a target gene, indicating a direct tethering mechanism. Being able to manipulate gene position independently of other changes in differentiation revealed that repositioning contributes 1/3 to 2/3 of a gene's normal repression in myogenesis. Together, these NETs affect 37% of all genes changing expression during myogenesis, and their combined knockdown almost completely blocks myotube formation. This unequivocally demonstrates that NET-directed gene repositioning is critical for developmental gene regulation.