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

Pascual-Garcia, Pau; Debo, Brian; Aleman, Jennifer R.; Talamas, Jessica A.; Lan, Yemin; Nguyen, Nha; Won, Kyoung Jae; Capelson, Maya

doi:10.1016/j.molcel.2017.02.020

Cited by 121 publications

(215 citation statements)

References 85 publications

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“…These lamin aggregates could be relevant to disease states where nuclear import is compromised [91][92][93][94][95], laminopathies [96][97][98][99][100][101][102], or cellular stress [103]. ELYS is a multifunctional protein which has been shown to interact with chromatin, enhancers, and promoters [53, 104,105]. While we cannot eliminate the possibility that ELYS depletion affects transcription, the fact that reduced nuclear import and size resulting from ELYS depletion were rescued by importin a overexpression strongly argues that the nuclear size effects are import-mediated.…”

Section: Discussionmentioning

confidence: 99%

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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How intracellular organelles acquire their characteristic sizes is a fundamental question in cell biology. Given stereotypical changes in nuclear size in cancer, it is important to understand the mechanisms that control nuclear size in human cells. Using a high‐throughput imaging RNAi screen, we identify and mechanistically characterize ELYS, a nucleoporin required for post‐mitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. ELYS knockdown results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin α overexpression rescues nuclear size and lamin B2 import, while inhibiting importin α/β‐mediated nuclear import decreases nuclear size. Conversely, ELYS overexpression increases nuclear size, enriches nuclear lamin B2 at the nuclear periphery, and elevates NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. Thus, we identify ELYS as a novel positive effector of mammalian nuclear size and propose that nuclear size is sensitive to NPC density and nuclear import capacity.

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Section: Discussionmentioning

confidence: 99%

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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“…Interestingly, we also observed absence of SWI/SNF PPIs with the MLL3 complex in SCCOHT cells. The SWI/SNF complex and chromatin association with nuclear pores has also been demonstrated to facilitate transcriptional memory which primes higher expression of a gene after an initial induction [61][62][63] . The loss of nuclear pore interactions with the SCCOHT SWI/SNF complex may suggest a loss of transcriptional memory that could affect how SCCOHT cells respond to environmental stimuli.…”

Section: The Sccoht Residual Swi/snf Complex Has Reduced Interactionsmentioning

confidence: 99%

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Raupach

Garcia-Mansfield

Sharma

et al. 2019

Preprint

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Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations in SMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.Introduction:

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“…However, emerging evidence from model organisms such as Drosophila, C.elegans, and yeast, suggest that nucleoporins also regulate gene expression (3,(8)(9)(10)(11)(12). ChIP-chip (Chromatin immunoprecipitation followed by tiling microarray) revealed that nucleoporin Nup93 associates with human chromosomes 5, 7 and 16 in HeLa cells (13).…”

Section: Introductionmentioning

confidence: 99%

Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

Labade

Salvi

Karmodiya

et al. 2019

Preprint

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The nuclear pore complex (NPC) regulates nuclear transport of RNA and proteins. Also, nucleoporins regulate chromatin organization and gene expression. However, the role of nucleoporins in the temporal regulation of gene expression during differentiation is unclear.Here we investigated the role of nucleoporin Nup93, in regulating HOXA gene expression during differentiation. ChIP-Seq analysis revealed that Nup93 associates with genes involved in development and differentiation such as HOXA. Furthermore, Nup93 occupancy overlaps with the chromatin organizer -CTCF, suggesting a co-regulatory role of Nup93 and CTCF in HOXA gene regulation. Interestingly, Nup93 and CTCF showed antagonistic roles in regulating expression levels of genes at the 3' and 5' end of the HOXA gene cluster in undifferentiated cells. Furthermore, HOXA gene locus untethered from the nuclear periphery upon Nup93 but not CTCF depletion, consistent with its upregulation. In addition, occupancy of Nup93 and CTCF on HOXA gene locus progressively declined during differentiation but was re-enriched on HOXA on Day 21 of differentiation consistent with its re-repression. Remarkably, the HOXA gene locus relocates toward the nuclear periphery upon differentiation. In summary, this study reveals that Nup93 is a key modulator of the spatiotemporal dynamics and function of the HOXA gene locus during differentiation.

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

Cited by 121 publications

References 85 publications

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation

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