@article{14315, abstract = {During apoptosis, caspases degrade 8 out of ~30 nucleoporins to irreversibly demolish the nuclear pore complex. However, for poorly understood reasons, caspases are also activated during cell differentiation. Here, we show that sublethal activation of caspases during myogenesis results in the transient proteolysis of four peripheral Nups and one transmembrane Nup. ‘Trimmed’ NPCs become nuclear export-defective, and we identified in an unbiased manner several classes of cytoplasmic, plasma membrane, and mitochondrial proteins that rapidly accumulate in the nucleus. NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress. Our results suggest that caspases can reversibly modulate nuclear transport activity, which allows them to function as agents of cell differentiation and adaptation at sublethal levels.}, author = {Cho, Ukrae H. and Hetzer, Martin W}, issn = {2050-084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress}}, doi = {10.7554/eLife.89066}, volume = {12}, year = {2023}, } @article{12880, abstract = {Peripheral heterochromatin positioning depends on nuclear envelope associated proteins and repressive histone modifications. Here we show that overexpression (OE) of Lamin B1 (LmnB1) leads to the redistribution of peripheral heterochromatin into heterochromatic foci within the nucleoplasm. These changes represent a perturbation of heterochromatin binding at the nuclear periphery (NP) through a mechanism independent from altering other heterochromatin anchors or histone post-translational modifications. We further show that LmnB1 OE alters gene expression. These changes do not correlate with different levels of H3K9me3, but a significant number of the misregulated genes were likely mislocalized away from the NP upon LmnB1 OE. We also observed an enrichment of developmental processes amongst the upregulated genes. ~74% of these genes were normally repressed in our cell type, suggesting that LmnB1 OE promotes gene de-repression. This demonstrates a broader consequence of LmnB1 OE on cell fate, and highlights the importance of maintaining proper levels of LmnB1.}, author = {Kaneshiro, Jeanae M. and Capitanio, Juliana S. and Hetzer, Martin W}, issn = {1949-1042}, journal = {Nucleus}, number = {1}, publisher = {Taylor & Francis}, title = {{Lamin B1 overexpression alters chromatin organization and gene expression}}, doi = {10.1080/19491034.2023.2202548}, volume = {14}, year = {2023}, } @article{11051, abstract = {Nuclear pore complexes (NPCs) bridge the nucleus and the cytoplasm and are indispensable for crucial cellular activities, such as bidirectional molecular trafficking and gene transcription regulation. The discovery of long-lived proteins (LLPs) in NPCs from postmitotic cells raises the exciting possibility that the maintenance of NPC integrity might play an inherent role in lifelong cell function. Age-dependent deterioration of NPCs and loss of nuclear integrity have been linked to age-related decline in postmitotic cell function and degenerative diseases. In this review, we discuss our current understanding of NPC maintenance in proliferating and postmitotic cells, and how malfunction of nucleoporins (Nups) might contribute to the pathogenesis of various neurodegenerative and cardiovascular diseases.}, author = {Liu, Jinqiang and HETZER, Martin W}, issn = {0962-8924}, journal = {Trends in Cell Biology}, keywords = {Cell Biology}, number = {3}, pages = {P216--227}, publisher = {Elsevier}, title = {{Nuclear pore complex maintenance and implications for age-related diseases}}, doi = {10.1016/j.tcb.2021.10.001}, volume = {32}, year = {2022}, } @article{11052, abstract = {In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.}, author = {Krishna, Shefali and Arrojo e Drigo, Rafael and Capitanio, Juliana S. and Ramachandra, Ranjan and Ellisman, Mark and HETZER, Martin W}, issn = {1534-5807}, journal = {Developmental Cell}, keywords = {Developmental Biology, Cell Biology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology}, number = {21}, pages = {P2952--2965.e9}, publisher = {Elsevier}, title = {{Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain}}, doi = {10.1016/j.devcel.2021.10.008}, volume = {56}, year = {2021}, } @article{11053, abstract = {Understanding basic mechanisms of aging holds great promise for developing interventions that prevent or delay many age-related declines and diseases simultaneously to increase human healthspan. However, a major confounding factor in aging research is the heterogeneity of the aging process itself. At the organismal level, it is clear that chronological age does not always predict biological age or susceptibility to frailty or pathology. While genetics and environment are major factors driving variable rates of aging, additional complexity arises because different organs, tissues, and cell types are intrinsically heterogeneous and exhibit different aging trajectories normally or in response to the stresses of the aging process (e.g., damage accumulation). Tackling the heterogeneity of aging requires new and specialized tools (e.g., single-cell analyses, mass spectrometry-based approaches, and advanced imaging) to identify novel signatures of aging across scales. Cutting-edge computational approaches are then needed to integrate these disparate datasets and elucidate network interactions between known aging hallmarks. There is also a need for improved, human cell-based models of aging to ensure that basic research findings are relevant to human aging and healthspan interventions. The San Diego Nathan Shock Center (SD-NSC) provides access to cutting-edge scientific resources to facilitate the study of the heterogeneity of aging in general and to promote the use of novel human cell models of aging. The center also has a robust Research Development Core that funds pilot projects on the heterogeneity of aging and organizes innovative training activities, including workshops and a personalized mentoring program, to help investigators new to the aging field succeed. Finally, the SD-NSC participates in outreach activities to educate the general community about the importance of aging research and promote the need for basic biology of aging research in particular.}, author = {Shadel, Gerald S. and Adams, Peter D. and Berggren, W. Travis and Diedrich, Jolene K. and Diffenderfer, Kenneth E. and Gage, Fred H. and Hah, Nasun and Hansen, Malene and HETZER, Martin W and Molina, Anthony J. A. and Manor, Uri and Marek, Kurt and O’Keefe, David D. and Pinto, Antonio F. M. and Sacco, Alessandra and Sharpee, Tatyana O. and Shokriev, Maxim N. and Zambetti, Stefania}, issn = {2509-2715}, journal = {GeroScience}, keywords = {Geriatrics and Gerontology, Aging}, number = {5}, pages = {2139--2148}, publisher = {Springer Nature}, title = {{The San Diego Nathan Shock Center: Tackling the heterogeneity of aging}}, doi = {10.1007/s11357-021-00426-x}, volume = {43}, year = {2021}, } @article{11054, abstract = {In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging.}, author = {Cho, Ukrae H. and HETZER, Martin W}, issn = {0896-6273}, journal = {Neuron}, keywords = {General Neuroscience}, number = {6}, pages = {899--911}, publisher = {Elsevier}, title = {{Nuclear periphery takes center stage: The role of nuclear pore complexes in cell identity and aging}}, doi = {10.1016/j.neuron.2020.05.031}, volume = {106}, year = {2020}, } @article{11055, abstract = {Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP)−4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.}, author = {Bersini, Simone and Schulte, Roberta and Huang, Ling and Tsai, Hannah and HETZER, Martin W}, issn = {2050-084X}, journal = {eLife}, keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience}, publisher = {eLife Sciences Publications}, title = {{Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and Hutchinson-Gilford progeria syndrome}}, doi = {10.7554/elife.54383}, volume = {9}, year = {2020}, } @article{11056, abstract = {Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs). Long-living human microvascular networks embedding VECs and fibroblasts from skin biopsies are generated. RNA-seq, secretome analyses, and microfluidic assays demonstrate that fibroblasts from young donors restore the functionality of aged endothelial cells, an effect also achieved by serum from young donors. New biomarkers of vascular aging are validated in human biopsies and it is shown that young serum induces angiopoietin-like-4, which can restore compromised vascular barriers. This strategy is then employed to characterize transcriptional/functional changes induced on the blood–brain barrier by AD serum, demonstrating the importance of PTP4A3 in the regulation of permeability. Features of vascular degeneration during aging and AD are recapitulated, and a tool to identify novel biomarkers that can be exploited to develop future therapeutics modulating vascular function is established.}, author = {Bersini, Simone and Arrojo e Drigo, Rafael and Huang, Ling and Shokhirev, Maxim N. and HETZER, Martin W}, issn = {2366-7478}, journal = {Advanced Biosystems}, keywords = {General Biochemistry, Genetics and Molecular Biology, Biomedical Engineering, Biomaterials}, number = {5}, publisher = {Wiley}, title = {{Transcriptional and functional changes of the human microvasculature during physiological aging and Alzheimer disease}}, doi = {10.1002/adbi.202000044}, volume = {4}, year = {2020}, } @article{11057, abstract = {During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division.}, author = {Kang, Hyeseon and Shokhirev, Maxim N. and Xu, Zhichao and Chandran, Sahaana and Dixon, Jesse R. and HETZER, Martin W}, issn = {0890-9369}, journal = {Genes & Development}, keywords = {Developmental Biology, Genetics}, number = {13-14}, pages = {913--930}, publisher = {Cold Spring Harbor Laboratory Press}, title = {{Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation}}, doi = {10.1101/gad.335794.119}, volume = {34}, year = {2020}, } @article{11058, abstract = {Nucleoporin 93 (Nup93) expression inversely correlates with the survival of triple-negative breast cancer patients. However, our knowledge of Nup93 function in breast cancer besides its role as structural component of the nuclear pore complex is not understood. Combination of functional assays and genetic analyses suggested that chromatin interaction of Nup93 partially modulates the expression of genes associated with actin cytoskeleton remodeling and epithelial to mesenchymal transition, resulting in impaired invasion of triple-negative, claudin-low breast cancer cells. Nup93 depletion induced stress fiber formation associated with reduced cell migration/proliferation and impaired expression of mesenchymal-like genes. Silencing LIMCH1, a gene responsible for actin cytoskeleton remodeling and up-regulated upon Nup93 depletion, partially restored the invasive phenotype of cancer cells. Loss of Nup93 led to significant defects in tumor establishment/propagation in vivo, whereas patient samples revealed that high Nup93 and low LIMCH1 expression correlate with late tumor stage. Our approach identified Nup93 as contributor of triple-negative, claudin-low breast cancer cell invasion and paves the way to study the role of nuclear envelope proteins during breast cancer tumorigenesis.}, author = {Bersini, Simone and Lytle, Nikki K and Schulte, Roberta and Huang, Ling and Wahl, Geoffrey M and HETZER, Martin W}, issn = {2575-1077}, journal = {Life Science Alliance}, keywords = {Health, Toxicology and Mutagenesis, Plant Science, Biochemistry, Genetics and Molecular Biology (miscellaneous), Ecology}, number = {1}, publisher = {Life Science Alliance}, title = {{Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling}}, doi = {10.26508/lsa.201900623}, volume = {3}, year = {2020}, } @article{11059, abstract = {The genome is packaged and organized nonrandomly within the 3D space of the nucleus to promote efficient gene expression and to faithfully maintain silencing of heterochromatin. The genome is enclosed within the nucleus by the nuclear envelope membrane, which contains a set of proteins that actively participate in chromatin organization and gene regulation. Technological advances are providing views of genome organization at unprecedented resolution and are beginning to reveal the ways that cells co-opt the structures of the nuclear periphery for nuclear organization and gene regulation. These genome regulatory roles of proteins of the nuclear periphery have important influences on development, disease and ageing.}, author = {Buchwalter, Abigail and Kaneshiro, Jeanae M. and HETZER, Martin W}, issn = {1471-0064}, journal = {Nature Reviews Genetics}, keywords = {Genetics (clinical), Genetics, Molecular Biology}, number = {1}, pages = {39--50}, publisher = {Springer Nature}, title = {{Coaching from the sidelines: The nuclear periphery in genome regulation}}, doi = {10.1038/s41576-018-0063-5}, volume = {20}, year = {2019}, } @article{11060, abstract = {The inner nuclear membrane (INM) is a subdomain of the endoplasmic reticulum (ER) that is gated by the nuclear pore complex. It is unknown whether proteins of the INM and ER are degraded through shared or distinct pathways in mammalian cells. We applied dynamic proteomics to profile protein half-lives and report that INM and ER residents turn over at similar rates, indicating that the INM’s unique topology is not a barrier to turnover. Using a microscopy approach, we observed that the proteasome can degrade INM proteins in situ. However, we also uncovered evidence for selective, vesicular transport-mediated turnover of a single INM protein, emerin, that is potentiated by ER stress. Emerin is rapidly cleared from the INM by a mechanism that requires emerin’s LEM domain to mediate vesicular trafficking to lysosomes. This work demonstrates that the INM can be dynamically remodeled in response to environmental inputs.}, author = {Buchwalter, Abigail and Schulte, Roberta and Tsai, Hsiao and Capitanio, Juliana and HETZER, Martin W}, issn = {2050-084X}, journal = {eLife}, keywords = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience}, publisher = {eLife Sciences Publications}, title = {{Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress}}, doi = {10.7554/elife.49796}, volume = {8}, year = {2019}, } @article{11061, abstract = {Many adult tissues contain postmitotic cells as old as the host organism. The only organelle that does not turn over in these cells is the nucleus, and its maintenance represents a formidable challenge, as it harbors regulatory proteins that persist throughout adulthood. Here we developed strategies to visualize two classes of such long-lived proteins, histones and nucleoporins, to understand the function of protein longevity in nuclear maintenance. Genome-wide mapping of histones revealed specific enrichment of long-lived variants at silent gene loci. Interestingly, nuclear pores are maintained by piecemeal replacement of subunits, resulting in mosaic complexes composed of polypeptides with vastly different ages. In contrast, nondividing quiescent cells remove old nuclear pores in an ESCRT-dependent manner. Our findings reveal distinct molecular strategies of nuclear maintenance, linking lifelong protein persistence to gene regulation and nuclear integrity.}, author = {Toyama, Brandon H. and Arrojo e Drigo, Rafael and Lev-Ram, Varda and Ramachandra, Ranjan and Deerinck, Thomas J. and Lechene, Claude and Ellisman, Mark H. and HETZER, Martin W}, issn = {1540-8140}, journal = {Journal of Cell Biology}, keywords = {Cell Biology}, number = {2}, pages = {433--444}, publisher = {Rockefeller University Press}, title = {{Visualization of long-lived proteins reveals age mosaicism within nuclei of postmitotic cells}}, doi = {10.1083/jcb.201809123}, volume = {218}, year = {2019}, } @article{11062, abstract = {Most neurons are not replaced during an animal’s lifetime. This nondividing state is characterized by extreme longevity and age-dependent decline of key regulatory proteins. To study the lifespans of cells and proteins in adult tissues, we combined isotope labeling of mice with a hybrid imaging method (MIMS-EM). Using 15N mapping, we show that liver and pancreas are composed of cells with vastly different ages, many as old as the animal. Strikingly, we also found that a subset of fibroblasts and endothelial cells, both known for their replicative potential, are characterized by the absence of cell division during adulthood. In addition, we show that the primary cilia of beta cells and neurons contains different structural regions with vastly different lifespans. Based on these results, we propose that age mosaicism across multiple scales is a fundamental principle of adult tissue, cell, and protein complex organization.}, author = {Arrojo e Drigo, Rafael and Lev-Ram, Varda and Tyagi, Swati and Ramachandra, Ranjan and Deerinck, Thomas and Bushong, Eric and Phan, Sebastien and Orphan, Victoria and Lechene, Claude and Ellisman, Mark H. and HETZER, Martin W}, issn = {1550-4131}, journal = {Cell Metabolism}, keywords = {Cell Biology, Molecular Biology, Physiology}, number = {2}, pages = {343--351.e3}, publisher = {Elsevier}, title = {{Age mosaicism across multiple scales in adult tissues}}, doi = {10.1016/j.cmet.2019.05.010}, volume = {30}, year = {2019}, } @misc{13079, abstract = {The inner nuclear membrane (INM) is a subdomain of the endoplasmic reticulum (ER) that is gated by the nuclear pore complex. It is unknown whether proteins of the INM and ER are degraded through shared or distinct pathways in mammalian cells. We applied dynamic proteomics to profile protein half-lives and report that INM and ER residents turn over at similar rates, indicating that the INM’s unique topology is not a barrier to turnover. Using a microscopy approach, we observed that the proteasome can degrade INM proteins in situ. However, we also uncovered evidence for selective, vesicular transport-mediated turnover of a single INM protein, emerin, that is potentiated by ER stress. Emerin is rapidly cleared from the INM by a mechanism that requires emerin’s LEM domain to mediate vesicular trafficking to lysosomes. This work demonstrates that the INM can be dynamically remodeled in response to environmental inputs.}, author = {Buchwalter, Abigail and Schulte, Roberta and Tsai, Hsiao and Capitanio, Juliana and HETZER, Martin W}, publisher = {Dryad}, title = {{Data from: Selective clearance of the inner nuclear membrane protein emerin by vesicular transport during ER stress}}, doi = {10.5061/DRYAD.N0R525H}, year = {2019}, } @article{11063, abstract = {The total number of nuclear pore complexes (NPCs) per nucleus varies greatly between different cell types and is known to change during cell differentiation and cell transformation. However, the underlying mechanisms that control how many nuclear transport channels are assembled into a given nuclear envelope remain unclear. Here, we report that depletion of the NPC basket protein Tpr, but not Nup153, dramatically increases the total NPC number in various cell types. This negative regulation of Tpr occurs via a phosphorylation cascade of extracellular signal-regulated kinase (ERK), the central kinase of the mitogen-activated protein kinase (MAPK) pathway. Tpr serves as a scaffold for ERK to phosphorylate the nucleoporin (Nup) Nup153, which is critical for early stages of NPC biogenesis. Our results reveal a critical role of the Nup Tpr in coordinating signal transduction pathways during cell proliferation and the dynamic organization of the nucleus.}, author = {McCloskey, Asako and Ibarra, Arkaitz and HETZER, Martin W}, issn = {0890-9369}, journal = {Genes & Development}, keywords = {Developmental Biology, Genetics}, number = {19-20}, pages = {1321--1331}, publisher = {Cold Spring Harbor Laboratory}, title = {{Tpr regulates the total number of nuclear pore complexes per cell nucleus}}, doi = {10.1101/gad.315523.118}, volume = {32}, year = {2018}, } @article{11064, abstract = {Biomarkers of aging can be used to assess the health of individuals and to study aging and age-related diseases. We generate a large dataset of genome-wide RNA-seq profiles of human dermal fibroblasts from 133 people aged 1 to 94 years old to test whether signatures of aging are encoded within the transcriptome. We develop an ensemble machine learning method that predicts age to a median error of 4 years, outperforming previous methods used to predict age. The ensemble was further validated by testing it on ten progeria patients, and our method is the only one that predicts accelerated aging in these patients.}, author = {Fleischer, Jason G. and Schulte, Roberta and Tsai, Hsiao H. and Tyagi, Swati and Ibarra, Arkaitz and Shokhirev, Maxim N. and Huang, Ling and HETZER, Martin W and Navlakha, Saket}, issn = {1474-760X}, journal = {Genome Biology}, publisher = {BioMed Central}, title = {{Predicting age from the transcriptome of human dermal fibroblasts}}, doi = {10.1186/s13059-018-1599-6}, volume = {19}, year = {2018}, } @article{11065, abstract = {Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging.}, author = {Buchwalter, Abigail and HETZER, Martin W}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry}, publisher = {Springer Nature}, title = {{Nucleolar expansion and elevated protein translation in premature aging}}, doi = {10.1038/s41467-017-00322-z}, volume = {8}, year = {2017}, } @article{11066, abstract = {Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.}, author = {Franks, Tobias M. and McCloskey, Asako and Shokhirev, Maxim Nikolaievich and Benner, Chris and Rathore, Annie and HETZER, Martin W}, issn = {0890-9369}, journal = {Genes & Development}, keywords = {Developmental Biology, Genetics}, number = {22}, pages = {2222--2234}, publisher = {Cold Spring Harbor Laboratory}, title = {{Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells}}, doi = {10.1101/gad.306753.117}, volume = {31}, year = {2017}, } @article{11067, abstract = {Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate.}, author = {Toda, Tomohisa and Hsu, Jonathan Y. and Linker, Sara B. and Hu, Lauren and Schafer, Simon T. and Mertens, Jerome and Jacinto, Filipe V. and HETZER, Martin W and Gage, Fred H.}, issn = {1934-5909}, journal = {Cell Stem Cell}, keywords = {Cell Biology, Genetics, Molecular Medicine}, number = {5}, pages = {618--634.e7}, publisher = {Elsevier}, title = {{Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells}}, doi = {10.1016/j.stem.2017.08.012}, volume = {21}, year = {2017}, }