Abstract
Faithful execution of developmental gene expression programs occurs at multiple levels and involves many different components such as transcription factors, histone-modification enzymes, and mRNA processing proteins. Recent evidence suggests that nucleoporins, well known components that control nucleo-cytoplasmic trafficking, have wide-ranging functions in developmental gene regulation that potentially extend beyond their role in nuclear transport. Whether the unexpected role of nuclear pore proteins in transcription regulation, which initially has been described in fungi and flies, also applies to human cells is unknown. Here we show at a genome-wide level that the nuclear pore protein NUP98 associates with developmentally regulated genes active during human embryonic stem cell differentiation. Overexpression of a dominant negative fragment of NUP98 levels decreases expression levels of NUP98-bound genes. In addition, we identify two modes of developmental gene regulation by NUP98 that are differentiated by the spatial localization of NUP98 target genes. Genes in the initial stage of developmental induction can associate with NUP98 that is embedded in the nuclear pores at the nuclear periphery. Alternatively, genes that are highly induced can interact with NUP98 in the nuclear interior, away from the nuclear pores. This work demonstrates for the first time that NUP98 dynamically associates with the human genome during differentiation, revealing a role of a nuclear pore protein in regulating developmental gene expression programs.
Highlights
In eukaryotes, the nuclear envelope (NE) forms a membrane barrier around the nuclear genome
To test whether NUP98 can bind to the mammalian genome during cell differentiation, we performed ChIP-Seq experiments on cultured human embryonic stem cells (ESCs), neural progenitor cells (NeuPCs) that were differentiated in vitro from ESCs, and neurons that were differentiated in vitro from NeuPCs
We found that all 24 genes were upregulated when ESCs were differentiated to NeuPCs, consistent with the genome-wide correlation analysis and supporting a role of NUP98 in the induction of transcription (Figure 3D)
Summary
The nuclear envelope (NE) forms a membrane barrier around the nuclear genome. Initial electron microscopy studies suggested that nuclear pore complexes associate with decondensed, transcriptionally active euchromatin in an otherwise highly condensed, heterochromatic nuclear periphery [5,6,7]. Based on these observations, it has been proposed that nuclear pore complexes may interact with active genes to promote the export of their transcripts [7]. In Drosophila embryonic culture cells, Nups predominantly interacted with active genes inside the nucleoplasm, whereas the nuclear pore complexes at the nuclear periphery was associated with repressed genes [17]
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