Tissue-specific gene repositioning by muscle nuclear membrane proteins enhances repression of critical developmental genes during myogenesis

Michael I. Robson, Jose I. de las Heras, Rafal Czapiewski, Phú Lê Thành, Daniel G. Booth, David A. Kelly, Shaun Webb, Alastair R W Kerr, Eric C. Schirmer

Research output: Contribution to journalArticlepeer-review

Abstract

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 1/2 to 1/2 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.

Original languageEnglish
Pages (from-to)834-847
Number of pages14
JournalMolecular Cell
Volume62
Issue number6
Early online date2 Jun 2016
DOIs
Publication statusPublished - 16 Jun 2016

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