SummaryWhether 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 ⅓ to ⅔ 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.

HighlightsX-linked female presenting with EDMD1 not explained by uneven X-inactivation.First EDMD blood phenotype with highly lobulated lymphocytes in EDMD1 patient.Found high incidence of spontaneous differentiation in cultured patient myoblasts.Faster proliferation of emerin-null than emerin-positive EDMD1 patient myoblasts.Loss of satellite cells from the above might explain EDMD pathology.

HighlightsAltered distribution of EDMD-linked proteins is not a general characteristic of EDMD.Tissue-specific proteins exhibit altered distributions in some EDMD patients.Variation in redistributed proteins in EDMD may underlie its clinical variability.