Nuclear Pores Regulate Muscle Development and Maintenance by Assembling a Localized Mef2C Complex

Abstract

SUMMARY Nuclear pore complexes (NPCs) are multiprotein channels connecting the nucleus with the cytoplasm. NPCs have been shown to have tissue-specific composition, suggesting that their function can be specialized. However, the physiological roles of NPC composition changes and their impacts on cellular processes remain unclear. Here we show that the addition of the Nup210 nucleoporin to NPCs during myoblast differentiation results in assembly of an Mef2C transcriptional complex required for efficient expression of muscle structural genes and microRNAs. We show that this NPC-localized complex is essential for muscle growth, myofiber maturation, and muscle cell survival and that alterations in its activity result in muscle degeneration. Our findings suggest that NPCs regulate the activity of functional gene groups by acting as scaffolds that promote the local assembly of tissue-specific transcription complexes and show how nuclear pore composition changes can be exploited to regulate gene expression at the nuclear periphery.

Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

“…Dam ID analyses of genome-wide interaction of Nup93 revealed its association with super-enhancers, that regulate expression of cell identity genes (4). Nucleoporin -Nup210, shows tissue-specific expression and is involved in muscle cell differentiation, maturation and survival of differentiated cells (14,15). Nup50 depletion inhibits differentiation of C2C12 cells into myotubes (16).…”

Transcriptional memory in skeletal muscle. Don't forget (to) exercise

“…Similarly, Nup‐chromatin interactions are also crucial for temporal and spatial regulation of structural gene expression programs in skeletal muscle. During skeletal muscle differentiation, the muscle‐specific Nup210 has been shown to become integrated into the NPC to scaffold the TF myocyte‐specific enhancer factor 2C (Mef2C) at the NPC, promoting activation of target genes involved in sarcomere assembly, myofiber maturation, and muscle growth (Raices et al, 2017). Remarkably, this muscle‐specific NPC‐tethered gene expression network not only encompasses protein‐coding genes but also distinct species of muscle‐specific microRNAs.…”

“…During skeletal muscle differentiation, the muscle-specific Nup210 has been shown to become integrated into the NPC to scaffold the TF myocyte-specific enhancer factor 2C (Mef2C) at the NPC, promoting activation of target genes involved in sarcomere assembly, myofiber maturation, and muscle growth (Raices et al, 2017).…”

Mice deficient in nucleoporin Nup210 develop peripheral T cell alterations

“…More recently, it was shown that shRNA knockdown of Nup210 in myoblasts and embryonic stem cells induced apoptosis and completely abrogated their differentiation into myotubes and neuroprogenitor cells [16]. Further studies have suggested that Nup210 is acting as a scaffolding protein for transcriptional complexes such as Mef2C, and that the tissue-specific expression is most likely a driver for the specialisation of NPCs in different cell types, thereby playing a role in the regulation of cell fate [17]. This cellular function has been studied in most detail in myocyte culture [17], however the role of NUP210 at the organism level has not been studied.…”