Abstract
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.
Highlights
Repositioning certain developmentally important genes between the nuclear periphery and interior during differentiation correlates with changes in their expression state
NET39 Directs Chromosome 8 Repositioning In Myogenesis NET39 is induced early in myogenesis (Liu et al, 2009) and could reposition a subset of chromosomes to the nuclear periphery in fibroblasts (Zuleger et al, 2013)
This suggested that NET39— and potentially other muscle nuclear envelope transmembrane proteins (NETs)—might direct gene and chromosome positioning changes during myogenesis
Summary
Repositioning certain developmentally important genes between the nuclear periphery and interior during differentiation correlates with changes in their expression state. New genome-wide approaches have identified many developmentally important genes that change in their peripheral association during differentiation with correspondingly altered expression (Peric-Hupkes et al., 2010). These findings raise the questions: how are gene positioning patterns established and regulated during development, and, to what extent does altered nuclear position contribute to changes in a genes expression?. Little is known about the regulation of specific developmental gene repositioning to the periphery, nuclear envelope (NE) proteins clearly direct establishment of genome-wide patterns of peripheral heterochromatin organization. The near ubiquitous expression of lamins, LAP2b and LBR and the general nature of these interactions argue for other mechanisms to explain tissue-specific aspects of gene positioning
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