Nup153 Interacts with Sox2 to Enable Bimodal Gene Regulation and Maintenance of Neural Progenitor Cells

Abstract

Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.

Nup62‐mediated nuclear import of p63 in squamous cell carcinoma

“…Jacinto et al [5] then reported a role for the nucleoporin Nup153, which localizes to the nuclear basket and also exists outside of the pore in the nucleoplasm, in the regulation of ESC pluripotency. These observations were recently confirmed by Toda et al, [6] who further showed that neuroprogenitor cells require high expression of Nup153 for their maintenance. These observations were recently confirmed by Toda et al, [6] who further showed that neuroprogenitor cells require high expression of Nup153 for their maintenance.…”

“…Reduction of Nup153 expression in ESCs was shown to induce early neuronal differentiation, revealing a role for this nucleoporin in maintaining ESC stemness [5]. These observations were recently confirmed by Toda et al, [6] who further showed that neuroprogenitor cells require high expression of Nup153 for their maintenance.…”

“…Previous nucleoporins implicated in cell fate determination were shown to do so via regulation of gene transcription. While Nup-210 is essential for assembling a MEF2Ccontaining transcription complex at the nuclear periphery of muscle cells [4,10], Nup153 recruits PRC1 complexes and associates with Sox2 to repress ESC differentiation genes [5,6]. In this study, Hazawa et al report the regulation of cell proliferation and differentiation via modulation of the canonical function of nuclear pore complexes, the regulation of nucleo-cytoplasmic transport.…”

“…While Nup-210 is essential for assembling a MEF2Ccontaining transcription complex at the nuclear periphery of muscle cells [4,10], Nup153 recruits PRC1 complexes and associates with Sox2 to repress ESC differentiation genes [5,6]. While Nup-210 is essential for assembling a MEF2Ccontaining transcription complex at the nuclear periphery of muscle cells [4,10], Nup153 recruits PRC1 complexes and associates with Sox2 to repress ESC differentiation genes [5,6].…”

AAV Ablates Neurogenesis in the Adult Murine Hippocampus

“…Mouse NPCs were obtained from embryonic female C57BL/6 mouse hippocampus and cultured as described previously (Toda et al, 2017). NPCs were cultured in DMEM/F-12 supplemented with N2 and B27 (Invitrogen) in the presence of FGF2 (20 ng/ml), EGF (20 ng/ml), laminin (1 μg/ml) and heparin (5 μg/ml), using poly-ornithine/laminin (Sigma)-coated plastic plates.…”