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Nucleoporin-Mediated Regulation of Cell Identity Genes

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Nucleoporin-Mediated Regulation of Cell Identity Genes Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION The double-lipid bilayer of the NE is composed of the Nucleoporin-mediated outer nuclear membrane (ONM) and inner nuclear mem- regulation of cell identity genes brane (INM) and is perforated at multiple sites by NPCs. High-resolution images of the nuclear periphery of several Arkaitz Ibarra,1 Chris Benner,2,3 Swati Tyagi,1 human cell types show that the NE is mostly underlined Jonah Cool,1,4 and Martin W. Hetzer1 with heterochromatin, except at the NPCs (Capelson and Hetzer 2009). Consistent with these observations, the 1Molecular and Cell Biology Laboratory, 2Integrative Genomics lamins, a meshwork of intermediate filaments that under- and Bioinformatics Core, Salk Institute for Biological Studies, La lie the NE, interact with large transcriptionally repressed Jolla, California 92037, USA genomic regions at the nuclear periphery, the lamina-as- sociated domains (LADs) (Guelen et al. 2008). In contrast, The organization of the genome in the three-dimensional genomic regions at NPCs appear largely devoid of hetero- space of the nucleus is coupled with cell type-specific chromatin in human cells (Capelson and Hetzer 2009). gene expression. However, how nuclear architecture in- Each NPC is composed of several copies of ∼30 different fluences transcription that governs cell identity remains subunits, called nucleoporins (Nups). Structurally, the unknown. Here, we show that nuclear pore complex NPC is divided into a NE-embedded scaffold, comprised (NPC) components Nup93 and Nup153 bind superen- of the Nup93–Nup205 and Nup96–Nup107 subcom- hancers (SE), regulatory structures that drive the expres- plexes, and two peripheral structures, the cytoplasmic fil- sion of key genes that specify cell identity. We found aments and the nuclear basket. The latter extends into the that nucleoporin-associated SEs localize preferentially nuclear interior and is composed of Nup153 and Tpr ’ to the nuclear periphery, and absence of Nup153 and (D Angelo and Hetzer 2008). In addition to the well-char- acterized role of NPCs in the regulation of nucleocyto- Nup93 results in dramatic transcriptional changes of SE- plasmic transport of macromolecules, studies mainly in associated genes. Our results reveal a crucial role of yeast and Drosophila revealed that NPC components as- NPC components in the regulation of cell type-specifying sociate with specific genomic regions to positively or neg- genes and highlight nuclear architecture as a regulatory atively regulate the transcriptional activity of target genes layer of genome functions in cell fate. (for review, see Ibarra and Hetzer 2015). While most Nup– Supplemental material is available for this article. genome interactions in yeast occur at the NPC, in meta- zoans, dynamic Nups can also extensively interact Received July 17, 2016; revised version accepted October 7, 2016. with the genome away from the NPC (Capelson et al. 2010; Kalverda et al. 2010). In human cells, characteriza- tion of Nup–genome interactions is still in its infancy Cell type-specific gene expression relies on the accurate (Brown et al. 2008); nevertheless, the relevance of Nups spatial and temporal control of transcription. Thousands in the regulation of genome functions has been inferred of enhancers contribute to the execution of specific gene from the mutations of NPC components that lead to a expression programs. The activity of key genes crucial panel of tissue-specific pathologies (Capelson and Hetzer for cell type identity is driven by a small fraction of regu- 2009; Nofrini et al. 2016). It has been speculated that latory elements composed of clusters of enhancers, re- Nup functions in gene expression regulation might under- ferred to as stretch enhancers or superenhancers (SEs) lie their involvement in tissue-specific disorders (Raices ’ (Hnisz et al. 2013; Parker et al. 2013). The function of and D Angelo 2012). However, whether Nups could recog- enhancers is influenced by the topological organization nize and regulate the expression of cell type-specific genes of the genome, which is emerging as a major regulator in human cells remains unknown. in the maintenance of cell type-specific gene expression (Cavalli and Misteli 2013; Heinz et al. 2015). While the precise mechanisms underlying genome organization Results and Discussion remain under scrutiny, large-scale spatial chromosome ar- chitecture partially relies on interactions with the nuclear NPC and INM components interact with functionally envelope (NE) (Mekhail and Moazed 2010; Van de Vosse opposite chromatin regions at the NE et al. 2011). Components of the NE and nuclear pore com- To gain insights into the role of NE proteins in the regula- plexes (NPCs) associate with the genome to influence its tion of genome functions in human cells, we used the organization and gene expression (Van de Vosse et al. DamID (DNA adenine methyltransferase identification) 2011). However, the potential contribution of NE compo- technique (Guelen et al. 2008; Kalverda et al. 2010; Meule- nents in the regulation of cell type-specific transcriptional man et al. 2013; Jacinto et al. 2015) to identify interac- programs is still poorly understood. tions between NE components and the genome. We first validated this approach by generating genome interaction maps in U2OS cells for the Lamin B receptor (LBR), an INM protein that interacts with Lamin B and contributes [Keywords: nuclear architecture; nucleoporin; nuclear pore complex; cell identity; superenhancer; transcription] Present addresses: 3Department of Medicine, University of California at © 2016 Ibarra et al. This article is distributed exclusively by Cold Spring San Diego, San Diego, La Jolla, CA 92093, USA; 4Organovo Holdings, Harbor Laboratory Press for the first six months after the full-issue publi- Inc., San Diego, CA 92121, USA. cation date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After Corresponding author: [email protected] six months, it is available under a Creative Commons License (Attribu- Article published online ahead of print. Article and publication date are tion-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.287417.116. commons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 30:1–6 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/16; www.genesdev.org 1 Downloaded from genesdev.cshlp.org on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Ibarra et al. to the localization of heterochromatin to the nuclear tions and DNase I hypersensitivity site [DHS] maps) periphery in differentiated cells (Solovei et al. 2013). We features of LBR, Nup153, and Nup93 interactions with generated stable cell lines expressing the Dam fused to the genome. LBR-associated domains presented lower LBR or GFP as a reference. We found that LBR associated gene density, low mRNA expression levels, low chroma- with 1046 large chromosome segments with a median tin accessibility (DHSs), lower occupancy of the insulator size of 766 kb (Fig. 1A; Supplemental Fig. S1A). LBR-asso- protein CTCF, and low levels of the central histone ciated regions effectively recapitulate the Lamin B1 modifications found at active promoters (H3K4me3) and DamID interaction maps described in HT1080 cells (Meu- regulatory elements (H3K27ac) (Fig. 1C–E; Supplemental leman et al. 2013) and Tig3 cells (97% and 79% overlap, Fig. S1C–F). Instead, LBR-associated domains exhibi- respectively) (Fig. 1A; Guelen et al. 2008). This indicates ted higher levels of the repressive histone modifica- that, as expected, LBR associates with the LADs, sup- tion H3K9me2 (Fig. 1F). In contrast, Nup153 and Nup93 porting a robust conservation of genome contacts with interaction sites accumulated closer to transcription the nuclear lamina (Meuleman et al. 2013). Next, to ex- start sites than LBR LADs (Supplemental Fig. S1G), pand our understanding of NE–genome interactions, mostly in promoter-distal intergenic (∼53% of Nup153 we performed similar experiments with components of and 51% of Nup93 interactions) and intragenic (∼39% of the NPCs, such as the nuclear basket member Nup153 Nup153 and 40% of Nup93 interactions) regions (Fig. 1I; and the scaffold constituent Nup93. Using a Dam-GFP- Supplemental Fig. S1H). Nup153 and Nup93 interaction expressing cell line to correct for the effects of local chro- sites were enriched for histone modifications associated matin accessibility (Guelen et al. 2008), we identified with active transcription such as H3K4me3 and, pre- 1851 local genome interaction sites with the basket dominantly, H3K27ac, which marks putative enhancers component Nup153 (Fig. 1B,I). In addition, we detec- (e.g., up to ∼50.5% of Nup153 interaction sites occur ted 1021 interaction sites for the more secluded NPC at H3K27ac regions; P <<1×10−10) (Fig. 1J; Supplemental component Nup93 that accumulate in very close pro- Fig. S1I). Interaction sites of these Nups also correlated ximity to Nup153-binding sites (Fig. 1B; Supplemental with DHSs, which characterize active regulatory regions Fig. S1B), likely representing bona fide interactions with (Fig. 1J; Supplemental Fig. S1I; Song and Crawford 2010). the NPC. Furthermore, the top de novo motif identified within We next characterized the genomic, transcriptional Nup153-binding sites was the regulatory DNA sequence (mRNA sequencing [RNA-seq]), and chromatin (chro- AP1, supporting the idea that Nup153 interacts with ge- matin immunoprecipitation [ChIP] combined with high- nomic regulatory regions, including putative transcrip- throughput sequencing [ChIP-seq] of epigenetic modifica- tional enhancers (Supplemental Fig. S1J). C E G Nups interact with SEs A LBR H3K27Ac 5.4e-7 Nup93 Chr5 0.4 1.2e-5 0.2 3.6e-7 When we examined the distribution of NE– 1Mb 0 6e-6 1.8e-7 Peaks/bp -0.2 Peaks/bp genome interactions, Nup93 and Nup153 -0.4 per LAD boundary 0 per LAD boundary Average log2 binding ratio 0 -200-400 0200400 -200-400 0200400 -200-400 0200400 interactions were found to accumulate out- LBR D Expression F H3K9me2 H Nup153 2e-3 9e-7 side of LBR-defined LADs (Fig.
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