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Metazoan Nuclear Pores Provide a Scaffold for Poised Genes and Mediate Induced Enhancer-Promoter Contacts.

ABSTRACT: Nuclear pore complex components (Nups) have been implicated in transcriptional regulation, yet what regulatory steps are controlled by metazoan Nups remains unclear. We identified the presence of multiple Nups at promoters, enhancers, and insulators in the Drosophila genome. In line with this binding, we uncovered a functional role for Nup98 in mediating enhancer-promoter looping at ecdysone-inducible genes. These genes were found to be stably associated with nuclear pores before and after activation. Although changing levels of Nup98 disrupted enhancer-promoter contacts, it did not affect ongoing transcription but instead compromised subsequent transcriptional activation or transcriptional memory. In support of the enhancer-looping role, we found Nup98 to gain and retain physical interactions with architectural proteins upon stimulation with ecdysone. Together, our data identify Nups as a class of architectural proteins for enhancers and supports a model in which animal genomes use the nuclear pore as an organizing scaffold for inducible poised genes.

SUBMITTER: Pascual-Garcia P

PROVIDER: S-EPMC7439321 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Metazoan Nuclear Pores Provide a Scaffold for Poised Genes and Mediate Induced Enhancer-Promoter Contacts.

Pascual-Garcia Pau P Debo Brian B Aleman Jennifer R JR Talamas Jessica A JA Lan Yemin Y Nguyen Nha H NH Won Kyoung J KJ Capelson Maya M

Molecular cell 20170330 1

Nuclear pore complex components (Nups) have been implicated in transcriptional regulation, yet what regulatory steps are controlled by metazoan Nups remains unclear. We identified the presence of multiple Nups at promoters, enhancers, and insulators in the Drosophila genome. In line with this binding, we uncovered a functional role for Nup98 in mediating enhancer-promoter looping at ecdysone-inducible genes. These genes were found to be stably associated with nuclear pores before and after activ ...[more]

PMID: 28366641

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Project description:BackgroundGene expression programs are intimately linked to the interplay of active cis regulatory elements mediated by chromatin contacts and associated RNAs. Genome-wide association studies (GWAS) have identified many variants in these regulatory elements that can contribute to phenotypic diversity. However, the functional interpretation of these variants remains nontrivial due to the lack of chromatin contact information or limited contact resolution. Furthermore, the distribution and role of chromatin-associated RNAs in gene expression and chromatin conformation remain poorly understood. To address this, we first present a comprehensive interaction map of nuclear dynamics of 3D chromatin-chromatin interactions (H3K27ac BL-HiChIP) and RNA-chromatin interactions (GRID-seq) to reveal genomic variants that contribute to complex skeletal muscle traits.ResultsIn a genome-wide scan, we provide systematic fine mapping and gene prioritization from GWAS leading signals that underlie phenotypic variability of growth rate, meat quality, and carcass performance. A set of candidate functional variants and 54 target genes previously not detected were identified, with 71% of these candidate functional variants choosing to skip over their nearest gene to regulate the target gene in a long-range manner. The effects of three functional variants regulating KLF6 (related to days to 100 kg), MXRA8 (related to lean meat percentage), and TAF11 (related to loin muscle depth) were observed in two pig populations. Moreover, we find that this multi-omics interaction map consists of functional communities that are enriched in specific biological functions, and GWAS target genes can serve as core genes for exploring peripheral trait-relevant genes.ConclusionsOur results provide a valuable resource of candidate functional variants for complex skeletal muscle-related traits and establish an integrated approach to complement existing 3D genomics by exploiting RNA-chromatin and chromatin-chromatin interactions for future association studies.

Dataset Information

Metazoan Nuclear Pores Provide a Scaffold for Poised Genes and Mediate Induced Enhancer-Promoter Contacts.

Publications

Metazoan Nuclear Pores Provide a Scaffold for Poised Genes and Mediate Induced Enhancer-Promoter Contacts.

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