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Cell Reports

Felix Bormann, Manuel Rodríguez-Paredes, Felix Lasitschka, Dominic Edelmann, Tanja Musch, Axel Benner, Yehudit Bergman, Sebastian M Dieter, Claudia R Ball, Hanno Glimm, Heinz G Linhart, Frank Lyko
Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and, therefore, provide opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell types of origin with adenomas...
June 12, 2018: Cell Reports
Hui Shen, Juliann Shih, Daniel P Hollern, Linghua Wang, Reanne Bowlby, Satish K Tickoo, Vésteinn Thorsson, Andrew J Mungall, Yulia Newton, Apurva M Hegde, Joshua Armenia, Francisco Sánchez-Vega, John Pluta, Louise C Pyle, Rohit Mehra, Victor E Reuter, Guilherme Godoy, Jeffrey Jones, Carl S Shelley, Darren R Feldman, Daniel O Vidal, Davor Lessel, Tomislav Kulis, Flavio M Cárcano, Kristen M Leraas, Tara M Lichtenberg, Denise Brooks, Andrew D Cherniack, Juok Cho, David I Heiman, Katayoon Kasaian, Minwei Liu, Michael S Noble, Liu Xi, Hailei Zhang, Wanding Zhou, Jean C ZenKlusen, Carolyn M Hutter, Ina Felau, Jiashan Zhang, Nikolaus Schultz, Gad Getz, Matthew Meyerson, Joshua M Stuart, Rehan Akbani, David A Wheeler, Peter W Laird, Katherine L Nathanson, Victoria K Cortessis, Katherine A Hoadley
We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma...
June 12, 2018: Cell Reports
Roberto Magliozzi, Zunamys I Carrero, Teck Yew Low, Laurensia Yuniati, Christian Valdes-Quezada, Flore Kruiswijk, Koen van Wijk, Albert J R Heck, Catherine L Jackson, Daniele Guardavaccaro
Although much is known about how chromosome segregation is coupled to cell division, how intracellular organelles partition during mitotic division is poorly understood. We report that the phosphorylation-dependent degradation of the ARFGEF GBF1 regulates organelle trafficking during cell division. We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation...
June 12, 2018: Cell Reports
Joseph Thomas Worrall, Naoka Tamura, Alice Mazzagatti, Nadeem Shaikh, Tineke van Lingen, Bjorn Bakker, Diana Carolina Johanna Spierings, Elina Vladimirou, Floris Foijer, Sarah Elizabeth McClelland
A common assumption is that human chromosomes carry equal chances of mis-segregation during compromised cell division. Human chromosomes vary in multiple parameters that might generate bias, but technological limitations have precluded a comprehensive analysis of chromosome-specific aneuploidy. Here, by imaging specific centromeres coupled with high-throughput single-cell analysis as well as single-cell sequencing, we show that aneuploidy occurs non-randomly following common treatments to elevate chromosome mis-segregation...
June 12, 2018: Cell Reports
Chunyan Liao, Ryan Beveridge, Jessica J R Hudson, Jacob D Parker, Shih-Chieh Chiang, Swagat Ray, Mohamed E Ashour, Ian Sudbery, Mark J Dickman, Sherif F El-Khamisy
Genomic damage can feature DNA-protein crosslinks whereby their acute accumulation is utilized to treat cancer and progressive accumulation causes neurodegeneration. This is typified by tyrosyl DNA phosphodiesterase 1 (TDP1), which repairs topoisomerase-mediated chromosomal breaks. Although TDP1 levels vary in multiple clinical settings, the mechanism underpinning this variation is unknown. We reveal that TDP1 is controlled by ubiquitylation and identify UCHL3 as the deubiquitylase that controls TDP1 proteostasis...
June 12, 2018: Cell Reports
Yang Zhao, Zhengjing Zhang, Jinghui Gao, Pengcheng Wang, Tao Hu, Zegang Wang, Yueh-Ju Hou, Yizhen Wan, Wenshan Liu, Shaojun Xie, Tianjiao Lu, Liang Xue, Yajie Liu, Alberto P Macho, W Andy Tao, Ray A Bressan, Jian-Kang Zhu
Abscisic acid (ABA) is an important phytohormone controlling responses to abiotic stresses and is sensed by proteins from the PYR/PYL/RCAR family. To explore the genetic contribution of PYLs toward ABA-dependent and ABA-independent processes, we generated and characterized high-order Arabidopsis mutants with mutations in the PYL family. We obtained a pyl quattuordecuple mutant and found that it was severely impaired in growth and failed to produce seeds. Thus, we carried out a detailed characterization of a pyl duodecuple mutant, pyr1pyl1/2/3/4/5/7/8/9/10/11/12...
June 12, 2018: Cell Reports
Sonja Kroschwald, Matthias C Munder, Shovamayee Maharana, Titus M Franzmann, Doris Richter, Martine Ruer, Anthony A Hyman, Simon Alberti
How cells adapt to varying environmental conditions is largely unknown. Here, we show that, in budding yeast, the RNA-binding and stress granule protein Pub1 has an intrinsic property to form condensates upon starvation or heat stress and that condensate formation is associated with cell-cycle arrest. Release from arrest coincides with condensate dissolution, which takes minutes (starvation) or hours (heat shock). In vitro reconstitution reveals that the different dissolution rates of starvation- and heat-induced condensates are due to their different material properties: starvation-induced Pub1 condensates form by liquid-liquid demixing and subsequently convert into reversible gel-like particles; heat-induced condensates are more solid-like and require chaperones for disaggregation...
June 12, 2018: Cell Reports
James R W Conway, Sean C Warren, David Herrmann, Kendelle J Murphy, Aurélie S Cazet, Claire Vennin, Robert F Shearer, Monica J Killen, Astrid Magenau, Pauline Mélénec, Mark Pinese, Max Nobis, Anaiis Zaratzian, Alice Boulghourjian, Andrew M Da Silva, Gonzalo Del Monte-Nieto, Arne S A Adam, Richard P Harvey, Jody J Haigh, Yingxiao Wang, David R Croucher, Owen J Sansom, Marina Pajic, C Elizabeth Caldon, Jennifer P Morton, Paul Timpson
Application of advanced intravital imaging facilitates dynamic monitoring of pathway activity upon therapeutic inhibition. Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors. To address this clinical problem, we have mapped tumor hypoxia by both immunofluorescence and phosphorescence lifetime imaging of oxygen-sensitive nanoparticles and demonstrate that these hypoxic regions move transiently around the tumor...
June 12, 2018: Cell Reports
Linford J B Briant, Michael S Dodd, Margarita V Chibalina, Nils J G Rorsman, Paul R V Johnson, Peter Carmeliet, Patrik Rorsman, Jakob G Knudsen
Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude...
June 12, 2018: Cell Reports
Soh Yamamoto, Kenta Kuramoto, Nan Wang, Xiaolei Situ, Medha Priyadarshini, Weiran Zhang, Jose Cordoba-Chacon, Brian T Layden, Congcong He
Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1F121A ) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy...
June 12, 2018: Cell Reports
Jeroen Witteveldt, Alasdair Ivens, Sara Macias
Type I interferons (IFNs) are central components of the antiviral response. Most cell types respond to viral infections by secreting IFNs, but the mechanisms that regulate correct expression of these cytokines are not completely understood. Here, we show that activation of the type I IFN response regulates the expression of miRNAs in a post-transcriptional manner. Activation of IFN expression alters the binding of the Microprocessor complex to pri-miRNAs, reducing its processing rate and thus leading to decreased levels of a subset of mature miRNAs in an IRF3-dependent manner...
June 12, 2018: Cell Reports
David Wang, Jason Quiros, Kelly Mahuron, Chien-Chun Pai, Valeria Ranzani, Arabella Young, Stephanie Silveria, Tory Harwin, Arbi Abnousian, Massimiliano Pagani, Michael D Rosenblum, Frederic Van Gool, Lawrence Fong, Jeffrey A Bluestone, Michel DuPage
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors...
June 12, 2018: Cell Reports
Kimmo Rantalainen, Zachary T Berndsen, Sasha Murrell, Liwei Cao, Oluwarotimi Omorodion, Jonathan L Torres, Mengyu Wu, Jeffrey Umotoy, Jeffrey Copps, Pascal Poignard, Elise Landais, James C Paulson, Ian A Wilson, Andrew B Ward
Broadly neutralizing antibodies (bnAbs) targeting the HIV envelope glycoprotein (Env) typically take years to develop. Longitudinal analyses of both neutralizing antibody lineages and viruses at serial time points during infection provide a basis for understanding the co-evolutionary contest between HIV and the humoral immune system. Here, we describe the structural characterization of an apex-targeting antibody lineage and autologous clade A viral Env from a donor in the Protocol C cohort. Comparison of Ab-Env complexes at early and late time points reveals that, within the antibody lineage, the CDRH3 loop rigidifies, the bnAb angle of approach steepens, and surface charges are mutated to accommodate glycan changes...
June 12, 2018: Cell Reports
Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Kimberly D Klarmann, Satyendra K Singh, Lei Sun, Shweta Singh, Yang Du, Vincenzo Coppola, Luke Stockwin, Nhu Nguyen, Lino Tessarollo, Leifur Thorsteinsson, Olafur E Sigurjonsson, Sveinn Gudmundsson, Thorunn Rafnar, John F Tisdale, Jonathan R Keller
Fetal globin genes are transcriptionally silenced during embryogenesis through hemoglobin switching. Strategies to derepress fetal globin expression in the adult could alleviate symptoms in sickle cell disease and β-thalassemia. We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells. Targeted deletion of Pogz in adult hematopoietic cells in vivo results in persistence of embryonic β-like globin expression without affecting erythroid development...
June 12, 2018: Cell Reports
Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, Yuzuru Kanakura
Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1- HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies...
June 12, 2018: Cell Reports
Wenjie Mao, Anna C Salzberg, Motokazu Uchigashima, Yuto Hasegawa, Hanno Hock, Masahiko Watanabe, Schahram Akbarian, Yuka Imamura Kawasawa, Kensuke Futai
Homeostatic synaptic downscaling reduces neuronal excitability by modulating the number of postsynaptic receptors. Histone modifications and the subsequent chromatin remodeling play critical roles in activity-dependent gene expression. Histone modification codes are recognized by chromatin readers that affect gene expression by altering chromatin structure. We show that L3mbtl1 (lethal 3 malignant brain tumor-like 1), a polycomb chromatin reader, is downregulated by neuronal activity and is essential for synaptic response and downscaling...
June 12, 2018: Cell Reports
Katelyn N Benthall, Stacie L Ong, Helen S Bateup
mTORC1 is a central signaling hub that integrates intra- and extracellular signals to regulate a variety of cellular metabolic processes. Mutations in regulators of mTORC1 lead to neurodevelopmental disorders associated with autism, which is characterized by repetitive, inflexible behaviors. These behaviors may result from alterations in striatal circuits that control motor learning and habit formation. However, the consequences of mTORC1 dysregulation on striatal neuron function are largely unknown. To investigate this, we deleted the mTORC1 negative regulator Tsc1 from identified striatonigral and striatopallidal neurons and examined how cell-autonomous upregulation of mTORC1 activity affects their morphology and physiology...
June 12, 2018: Cell Reports
Antoine Besnard, Tomer Langberg, Sally Levinson, Duong Chu, Cinzia Vicidomini, Kimberly N Scobie, Andrew J Dwork, Victoria Arango, Gorazd B Rosoklija, J John Mann, René Hen, E David Leonardo, Maura Boldrini, Amar Sahay
Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice...
June 12, 2018: Cell Reports
Calvin Ly, Alexandra C Greb, Lindsay P Cameron, Jonathan M Wong, Eden V Barragan, Paige C Wilson, Kyle F Burbach, Sina Soltanzadeh Zarandi, Alexander Sood, Michael R Paddy, Whitney C Duim, Megan Y Dennis, A Kimberley McAllister, Kassandra M Ori-McKenney, John A Gray, David E Olson
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology...
June 12, 2018: Cell Reports
Midori Ohta, Koki Watanabe, Tomoko Ashikawa, Yuka Nozaki, Satoko Yoshiba, Akatsuki Kimura, Daiju Kitagawa
The number of centrioles is tightly controlled to ensure bipolar spindle assembly, which is a prerequisite to maintain genome integrity. However, our understanding of the fundamental principle that governs the formation of a single procentriole per parental centriole is incomplete. Here, we show that the local restriction of Plk4, a master regulator of the procentriole formation, is achieved by a bimodal interaction of STIL with Plk4. We demonstrate that the conserved short coiled-coil region of STIL binds to and protects Plk4 from protein degradation at the site of procentriole formation...
June 12, 2018: Cell Reports
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