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Cell Reports

Marion Classe, Hui Yao, Roger Mouawad, Chad J Creighton, Alice Burgess, Frederick Allanic, Michel Wassef, Xavier Leroy, Benjamin Verillaud, Geoffrey Mortuaire, Franck Bielle, Christophe Le Tourneau, Jean-Emmanuel Kurtz, David Khayat, Xiaoping Su, Gabriel G Malouf
Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas...
October 16, 2018: Cell Reports
Vasiliki Lagou, Josselyn E Garcia-Perez, Ide Smets, Lies Van Horebeek, Marijne Vandebergh, Liye Chen, Klara Mallants, Teresa Prezzemolo, Kelly Hilven, Stephanie Humblet-Baron, Matthieu Moisse, Philip Van Damme, Guy Boeckxstaens, Paul Bowness, Bénédicte Dubois, James Dooley, Adrian Liston, An Goris
The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation...
October 16, 2018: Cell Reports
Aliki Perdikari, Germán Gastón Leparc, Miroslav Balaz, Nuno D Pires, Martin E Lidell, Wenfei Sun, Francesc Fernandez-Albert, Sebastian Müller, Nassila Akchiche, Hua Dong, Lucia Balazova, Lennart Opitz, Eva Röder, Holger Klein, Patrik Stefanicka, Lukas Varga, Pirjo Nuutila, Kirsi A Virtanen, Tarja Niemi, Markku Taittonen, Gottfried Rudofsky, Jozef Ukropec, Sven Enerbäck, Elia Stupka, Heike Neubauer, Christian Wolfrum
Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies...
October 16, 2018: Cell Reports
Rebeca Martín-García, Victor Arribas, Pedro M Coll, Mario Pinar, Raul A Viana, Sergio A Rincón, Jaime Correa-Bordes, Juan Carlos Ribas, Pilar Pérez
Paxillin is a scaffold protein that participates in focal adhesion signaling in mammalian cells. Fission yeast paxillin ortholog, Pxl1, is required for contractile actomyosin ring (CAR) integrity and collaborates with the β-glucan synthase Bgs1 in septum formation. We show here that Pxl1's main function is to recruit calcineurin (CN) phosphatase to the actomyosin ring; and thus the absence of either Pxl1 or calcineurin causes similar cytokinesis defects. In turn, CN participates in the dephosphorylation of the Cdc15 F-BAR protein, which recruits and concentrates Pxl1 at the CAR...
October 16, 2018: Cell Reports
Gabriele Micali, Jacopo Grilli, Jacopo Marchi, Matteo Osella, Marco Cosentino Lagomarsino
Understanding the classic problem of how single E. coli cells coordinate cell division with genome replication would open the way to addressing cell-cycle progression at the single-cell level. Recent studies produced new data, but the contrast in their conclusions and proposed mechanisms makes the emerging picture fragmented and unclear. Here, we re-evaluate available data and models, including generalizations based on the same assumptions. We show that although they provide useful insights, none of the proposed models captures all correlation patterns observed in data...
October 16, 2018: Cell Reports
Susana Simões-Sousa, Samantha Littler, Sarah L Thompson, Paul Minshall, Helen Whalley, Bjorn Bakker, Klaudyna Belkot, Daniela Moralli, Daniel Bronder, Anthony Tighe, Diana C J Spierings, Nourdine Bah, Joshua Graham, Louisa Nelson, Catherine M Green, Floris Foijer, Paul A Townsend, Stephen S Taylor
Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones...
October 16, 2018: Cell Reports
Gregory L Elison, Yuan Xue, Ruijie Song, Murat Acar
Despite advances made in understanding the effects of promoter structure on transcriptional activity, limited knowledge exists regarding the role played by chromatin architecture in transcription. Previous work hypothesized that transcription from the bidirectional GAL1/GAL10 promoter is controlled through looping of its UAS region around a nonstandard nucleosome. Here, by editing the GAL1/GAL10 promoter at high resolution, we provide insights into bidirectional expression control. We demonstrate that the first and fourth Gal4 binding sites within the UAS do not functionally contribute to promoter activation...
October 16, 2018: Cell Reports
Antonia De Maio, Hari Krishna Yalamanchili, Carolyn J Adamski, Vincenzo A Gennarino, Zhandong Liu, Jun Qin, Sung Y Jung, Ronald Richman, Harry Orr, Huda Y Zoghbi
RNA splicing entails the coordinated interaction of more than 150 proteins in the spliceosome, one of the most complex of the cell's molecular machines. We previously discovered that the RNA-binding motif protein 17 (RBM17), a component of the spliceosome, is essential for survival and cell maintenance. Here, we find that it interacts with the spliceosomal factors U2SURP and CHERP and that they reciprocally regulate each other's stability, both in mouse and in human cells. Individual knockdown of each of the three proteins induces overlapping changes in splicing and gene expression of transcripts enriched for RNA-processing factors...
October 16, 2018: Cell Reports
Scott A Hinger, Diana J Cha, Jeffrey L Franklin, James N Higginbotham, Yongchao Dou, Jie Ping, Lihua Shu, Nripesh Prasad, Shawn Levy, Bing Zhang, Qi Liu, Alissa M Weaver, Robert J Coffey, James G Patton
The regulation and functional roles of secreted coding and long noncoding RNAs (lncRNAs; >200 nt) are largely unknown. We previously showed that mutant KRAS colorectal cancer (CRC) cells release extracellular vesicles (EVs) containing distinct proteomes, microRNAs (miRNAs), and circular RNAs. Here, we comprehensively identify diverse classes of CRC extracellular long RNAs secreted in EVs and demonstrate differential export of specific RNAs. Distinct noncoding RNAs, including antisense transcripts and transcripts derived from pseudogenes, are enriched in EVs compared to cellular profiles...
October 16, 2018: Cell Reports
Yeji An, Jessica R Adams, Daniel P Hollern, Anthony Zhao, Stephen G Chang, Miki S Gams, Philip E D Chung, Xiaping He, Rhea Jangra, Juhi S Shah, Joanna Yang, Lauren A Beck, Nandini Raghuram, Katelyn J Kozma, Amanda J Loch, Wei Wang, Cheng Fan, Susan J Done, Eldad Zacksenhaus, Cynthia J Guidos, Charles M Perou, Sean E Egan
CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways...
October 16, 2018: Cell Reports
Lok Hei Chan, Lei Zhou, Kai Yu Ng, Tin Lok Wong, Terence K Lee, Rakesh Sharma, Jane H Loong, Yick Pang Ching, Yun-Fei Yuan, Dan Xie, Chung Mau Lo, Kwan Man, Benedetta Artegiani, Hans Clevers, Helen H Yan, Suet Yi Leung, Stéphane Richard, Xin-Yuan Guan, Michael S Y Huen, Stephanie Ma
Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/- ) mouse model...
October 16, 2018: Cell Reports
Saroj Chakraborty, Sarah Galla, Xi Cheng, Ji-Youn Yeo, Blair Mell, Vishal Singh, BengSan Yeoh, Piu Saha, Anna V Mathew, Matam Vijay-Kumar, Bina Joe
Dietary salt reduction and exercise are lifestyle modifications for salt-sensitive hypertensives. While exercise has prominent metabolic effects, salt has an adverse effect on metabolic syndrome, of which hypertension is a hallmark. We hypothesized that dietary salt impacts metabolism in a salt-sensitive model of hypertension. An untargeted metabolomic approach demonstrates lower circulating levels of the ketone body, beta-hydroxybutyrate (βOHB), in high salt-fed hypertensive rats. Despite the high salt intake, specific rescue of βOHB levels by nutritional supplementation of its precursor, 1,3-butanediol, attenuates hypertension and protects kidney function...
October 16, 2018: Cell Reports
Ryan O Walters, Esperanza Arias, Antonio Diaz, Emmanuel S Burgos, Fangxia Guan, Simoni Tiano, Kai Mao, Cara L Green, Yungping Qiu, Hardik Shah, Donghai Wang, Adam D Hudgins, Tahmineh Tabrizian, Valeria Tosti, David Shechter, Luigi Fontana, Irwin J Kurland, Nir Barzilai, Ana Maria Cuervo, Daniel E L Promislow, Derek M Huffman
A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network...
October 16, 2018: Cell Reports
Jacob A Berry, Anna Phan, Ronald L Davis
It remains unclear how memory engrams are altered by experience, such as new learning, to cause forgetting. Here, we report that short-term aversive memory in Drosophila is encoded by and retrieved from the mushroom body output neuron MBOn-γ2α'1. Pairing an odor with aversive electric shock creates a robust depression in the calcium response of MBOn-γ2α'1 and increases avoidance to the paired odor. Electric shock after learning, which activates the cognate dopamine neuron DAn-γ2α'1, restores the response properties of MBOn-γ2α'1 and causes behavioral forgetting...
October 16, 2018: Cell Reports
Alessio Attardo, Ju Lu, Takashi Kawashima, Hiroyuki Okuno, James E Fitzgerald, Haruhiko Bito, Mark J Schnitzer
Neural network remodeling underpins the ability to remember life experiences, but little is known about the long-term plasticity of neural populations. To study how the brain encodes episodic events, we used time-lapse two-photon microscopy and a fluorescent reporter of neural plasticity based on an enhanced form of the synaptic activity-responsive element (E-SARE) within the Arc promoter to track thousands of CA1 hippocampal pyramidal cells over weeks in mice that repeatedly encountered different environments...
October 16, 2018: Cell Reports
Takunori Minegishi, Yasuyuki Uesugi, Naoko Kaneko, Wataru Yoshida, Kazunobu Sawamoto, Naoyuki Inagaki
As an essential step for brain morphogenesis, neurons migrate via mechanical interactions with components of their environment such as neighboring cells and the extracellular matrix. However, the molecular mechanism by which neurons exert forces on their environment during migration remains poorly understood. Here, we show that shootin1b is expressed in migrating mouse olfactory interneurons and accumulates at their leading process growth cone. We demonstrate that shootin1b, by binding to cortactin and L1-CAM, couples F-actin retrograde flow and the adhesive substrate as a clutch molecule...
October 16, 2018: Cell Reports
Suddhasil Mookherjee, Holly Yu Chen, Kevin Isgrig, Wenhan Yu, Suja Hiriyanna, Rivka Levron, Tiansen Li, Peter Colosi, Wade Chien, Anand Swaroop, Zhijian Wu
Mutations in CEP290 cause ciliogenesis defects, leading to diverse clinical phenotypes, including Leber congenital amaurosis (LCA). Gene therapy for CEP290-associated diseases is hindered by the 7.4 kb CEP290 coding sequence, which is difficult to deliver in vivo. The multi-domain structure of the CEP290 protein suggests that a specific CEP290 domain may complement disease phenotypes. Thus, we constructed AAV vectors with overlapping CEP290 regions and evaluated their impact on photoreceptor degeneration in Cep290rd16/rd16 and Cep290rd16/rd16 ;Nrl-/- mice, two models of CEP290-LCA...
October 16, 2018: Cell Reports
Chengkang Zhang, Hyung Joo Lee, Anura Shrivastava, Ruipeng Wang, Travis J McQuiston, Sharon S Challberg, Brian A Pollok, Ting Wang
Despite substantial self-renewal capability in vivo, epithelial stem and progenitor cells located in various tissues expand for a few passages in vitro in feeder-free condition before they succumb to growth arrest. Here, we describe the EpiX method, which utilizes small molecules that inhibit PAK1-ROCK-Myosin II and TGF-β signaling to achieve over one trillion-fold expansion of human epithelial stem and progenitor cells from skin, airway, mammary, and prostate glands in the absence of feeder cells. Transcriptomic and epigenomic studies show that this condition helps epithelial cells to overcome stresses for continuous proliferation...
October 16, 2018: Cell Reports
Simon Joost, Tina Jacob, Xiaoyan Sun, Karl Annusver, Gioele La Manno, Inderpreet Sur, Maria Kasper
Epithelial tissues, such as the skin, rely on cellular plasticity of stem cells (SCs) from different niches to restore tissue function after injury. How these molecularly and functionally diverse SC populations respond to injury remains elusive. Here, we genetically labeled Lgr5- or Lgr6-expressing cells from the hair follicle bulge and interfollicular epidermis (IFE), respectively, and monitored their individual transcriptional adaptations during wound healing using single-cell transcriptomics. Both Lgr5 and Lgr6 progeny rapidly induced a genetic wound signature that, for Lgr5 progeny, included the remodeling of receptors to permit interactions with the wound environment, a property that Lgr6 progeny possessed even before wounding...
October 16, 2018: Cell Reports
Boksik Cha, Xin Geng, Md Riaj Mahamud, Jenny Y Zhang, Lijuan Chen, Wantae Kim, Eek-Hoon Jho, Yeunhee Kim, Dongwon Choi, J Brandon Dixon, Hong Chen, Young-Kwon Hong, Lorin Olson, Tae Hoon Kim, Bradley J Merrill, Michael J Davis, R Sathish Srinivasan
Wnt/β-catenin signaling is necessary for lymphatic vascular development. Oscillatory shear stress (OSS) enhances Wnt/β-catenin signaling in cultured lymphatic endothelial cells (LECs) to induce expression of the lymphedema-associated transcription factors GATA2 and FOXC2. However, the mechanisms by which OSS regulates Wnt/β-catenin signaling and GATA2 and FOXC2 expression are unknown. We show that OSS activates autocrine Wnt/β-catenin signaling in LECs in vitro. Tissue-specific deletion of Wntless, which is required for the secretion of Wnt ligands, reveals that LECs and vascular smooth muscle cells are complementary sources of Wnt ligands that regulate lymphatic vascular development in vivo...
October 16, 2018: Cell Reports
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