Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding at cis-regulatory elements and TAD boundaries

Abstract

ABSTRACTThe nuclear pore complex (NPC) components, nucleoporins (Nups), have been proposed to mediate spatial and temporal organization of chromatin during gene regulation. Nevertheless, we have little understanding on the molecular mechanisms that underlie Nup-mediated chromatin structure and transcription in mammals. Here, we show that Nucleoporin 153 (NUP153) interacts with the chromatin architectural proteins, CTCF and cohesin, and mediates their binding across cis-regulatory elements and TAD boundaries in mouse embryonic stem (ES) cells. NUP153 depletion results in altered CTCF and cohesin occupancy and differential gene expression. This function of NUP153 is most prevalent at the developmental genes that show bivalent chromatin state. To dissect the functional relevance of NUP153-mediated CTCF and cohesin binding during transcriptional activation or silencing, we utilized epidermal growth factor (EGF)-inducible immediate early genes (IEGs). We found that NUP153 binding at the cis-regulatory elements controls CTCF and cohesin binding and subsequent POL II pausing during the transcriptionally silent state. Furthermore, efficient and timely transcription initiation of IEGs relies on NUP153 and occurs around the nuclear periphery suggesting that NUP153 acts as an activator of IEG transcription. Collectively, these results uncover a key role for NUP153 in chromatin architecture and transcription by mediating CTCF and cohesin binding in mammalian cells. We propose that NUP153 links NPCs to chromatin architecture allowing developmental genes and IEGs that are poised to respond rapidly to developmental cues to be properly modulated.