James K Nuñez, Jin Chen, Greg C Pommier, J Zachery Cogan, Joseph M Replogle, Carmen Adriaens, Gokul N Ramadoss, Quanming Shi, King L Hung, Avi J Samelson, Angela N Pogson, James Y S Kim, Amanda Chung, Manuel D Leonetti, Howard Y Chang, Martin Kampmann, Bradley E Bernstein, Volker Hovestadt, Luke A Gilbert, Jonathan S Weissman
A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing...
April 7, 2021: Cell
Lianmin Chen, Daoming Wang, Sanzhima Garmaeva, Alexander Kurilshikov, Arnau Vich Vila, Ranko Gacesa, Trishla Sinha, Eran Segal, Rinse K Weersma, Cisca Wijmenga, Alexandra Zhernakova, Jingyuan Fu
By following up the gut microbiome, 51 human phenotypes and plasma levels of 1,183 metabolites in 338 individuals after 4 years, we characterize microbial stability and variation in relation to host physiology. Using these individual-specific and temporally stable microbial profiles, including bacterial SNPs and structural variations, we develop a microbial fingerprinting method that shows up to 85% accuracy in classifying metagenomic samples taken 4 years apart. Application of our fingerprinting method to the independent HMP cohort results in 95% accuracy for samples taken 1 year apart...
April 4, 2021: Cell
Stefan C Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock, Steven E Schumacher, Yu Fan, Matthew Fittall, Ruben M Drews, Xiaotong Yao, Thomas B K Watkins, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J Adams, Nicholas McGranahan, Charles Swanton, Gad Getz, Paul C Boutros, Marcin Imielinski, Rameen Beroukhim, S Cenk Sahinalp, Yuan Ji, Martin Peifer, Inigo Martincorena, Florian Markowetz, Ville Mustonen, Ke Yuan, Moritz Gerstung, Paul T Spellman, Wenyi Wang, Quaid D Morris, David C Wedge, Peter Van Loo
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions...
April 2, 2021: Cell
(no author information available yet)
Mary-Claire King's approach to genetics has had a major impact on breast and ovarian cancer and, more recently, mental illnesses including schizophrenia. Science writer Kendall Morgan talked with Mary-Claire, recipient of a 2021 Canada Gairdner International Award, about her life, her lengthy quest to discover the genetic basis of susceptibility to breast cancer, the struggles for women in science, and much more. An edited version of this conversation is presented below.
April 1, 2021: Cell
(no author information available yet)
Interdisciplinary work has played a key role in Dr. Elizabeth Eisenhauer's wide-ranging research contributions and leadership in cancer clinical trials, drug delivery, treatment standards, and research and prevention strategy. Cell editor Emma Yee talked with Dr. Eisenhauer, recipient of the 2021 Canada Gairdner Wightman Award, to learn more about the factors that influenced her work in cancer care and the lessons she learned along the way. This conversation is presented below, edited for clarity and length...
April 1, 2021: Cell
Michael Levin
How are individual cell behaviors coordinated toward invariant large-scale anatomical outcomes in development and regeneration despite unpredictable perturbations? Endogenous distributions of membrane potentials, produced by ion channels and gap junctions, are present across all tissues. These bioelectrical networks process morphogenetic information that controls gene expression, enabling cell collectives to make decisions about large-scale growth and form. Recent progress in the analysis and computational modeling of developmental bioelectric circuits and channelopathies reveals how cellular collectives cooperate toward organ-level structural order...
April 1, 2021: Cell
Jessica Sook Yuin Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A Wayman, Natasha N Gaudreault, David A Meekins, Sabarish V Indran, Igor Morozov, Jessie D Trujillo, Yesai S Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya Malysheva, Michiel J Thiecke, Siu-Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak-Yiu Lee, Wen-Chun Liu, Sonia Jangra, Alba Escalera, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David A Kaufman, Andre L Moreira, Mariano Carossino, Udeni B R Balasuriya, Minji Byun, Randy A Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K Chanda, Emily R Miraldi, Anand D Jeyasekharan, Benjamin R TenOever, Mikhail Spivakov, Matthew T Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A Richt, Ivan Marazzi
The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2...
March 30, 2021: Cell
(no author information available yet)
The events of the past year have underscored the serious and rapid threat that emerging viruses pose to global health. However, much of the rapid progress in understanding and combating SARS-CoV-2 was made possible because of the decades of important groundwork laid from researchers studying other emergent infectious diseases. The 2021 John Dirks Canada Gairdner Global Health award recognizes the contributions of Joseph Sriyal Malik Peiris and Yi Guan toward understanding the origins and options for control of newly emerging infectious disease outbreaks in Asia, notably zoonotic influenza and severe acute respiratory syndrome (SARS)...
March 30, 2021: Cell
Stephen O'Rahilly
The 2021 Gairdner Prize is awarded to Daniel Drucker, Joel Habener, and Jens Juul Holst for the discovery of novel peptides encoded in the proglucagon sequence and the establishment of their physiological roles. These discoveries underpinned the development of therapeutics that are now benefiting patients with type 2 diabetes and other disorders worldwide.
March 29, 2021: Cell
Jaime L Schneider, Jared H Rowe, Carolina Garcia-de-Alba, Carla F Kim, Arlene H Sharpe, Marcia C Haigis
The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer...
March 26, 2021: Cell
James F Pelletier, Lijie Sun, Kim S Wise, Nacyra Assad-Garcia, Bogumil J Karas, Thomas J Deerinck, Mark H Ellisman, Andreas Mershin, Neil Gershenfeld, Ray-Yuan Chuang, John I Glass, Elizabeth A Strychalski
Genomically minimal cells, such as JCVI-syn3.0, offer a platform to clarify genes underlying core physiological processes. Although this minimal cell includes genes essential for population growth, the physiology of its single cells remained uncharacterized. To investigate striking morphological variation in JCVI-syn3.0 cells, we present an approach to characterize cell propagation and determine genes affecting cell morphology. Microfluidic chemostats allowed observation of intrinsic cell dynamics that result in irregular morphologies...
March 26, 2021: Cell
Joseph Sriyal Malik Peiris
The past year has underscored the threat that emerging viruses pose to global health. The 2021 John Dirks Canada Gairdner Global Health award recognizes the contributions of Joseph Sriyal Malik Peiris and Yi Guan toward understanding the origins and options for control of newly emerging infectious disease outbreaks in Asia, notably zoonotic influenza and severe acute respiratory syndrome (SARS). Nicole Neuman of Cell corresponded with Malik Peiris about his path to studying emerging infectious diseases and the challenges of this work...
March 24, 2021: Cell
Mathieu Groussin, Mathilde Poyet, Ainara Sistiaga, Sean M Kearney, Katya Moniz, Mary Noel, Jeff Hooker, Sean M Gibbons, Laure Segurel, Alain Froment, Rihlat Said Mohamed, Alain Fezeu, Vanessa A Juimo, Sophie Lafosse, Francis E Tabe, Catherine Girard, Deborah Iqaluk, Le Thanh Tu Nguyen, B Jesse Shapiro, Jenni Lehtimäki, Lasse Ruokolainen, Pinja P Kettunen, Tommi Vatanen, Shani Sigwazi, Audax Mabulla, Manuel Domínguez-Rodrigo, Yvonne A Nartey, Adwoa Agyei-Nkansah, Amoako Duah, Yaw A Awuku, Kenneth A Valles, Shadrack O Asibey, Mary Y Afihene, Lewis R Roberts, Amelie Plymoth, Charles A Onyekwere, Roger E Summons, Ramnik J Xavier, Eric J Alm
Industrialization has impacted the human gut ecosystem, resulting in altered microbiome composition and diversity. Whether bacterial genomes may also adapt to the industrialization of their host populations remains largely unexplored. Here, we investigate the extent to which the rates and targets of horizontal gene transfer (HGT) vary across thousands of bacterial strains from 15 human populations spanning a range of industrialization. We show that HGTs have accumulated in the microbiome over recent host generations and that HGT occurs at high frequency within individuals...
March 23, 2021: Cell
Jixing Xia, Zhaojiang Guo, Zezhong Yang, Haolin Han, Shaoli Wang, Haifeng Xu, Xin Yang, Fengshan Yang, Qingjun Wu, Wen Xie, Xuguo Zhou, Wannes Dermauw, Ted C J Turlings, Youjun Zhang
Plants protect themselves with a vast array of toxic secondary metabolites, yet most plants serve as food for insects. The evolutionary processes that allow herbivorous insects to resist plant defenses remain largely unknown. The whitefly Bemisia tabaci is a cosmopolitan, highly polyphagous agricultural pest that vectors several serious plant pathogenic viruses and is an excellent model to probe the molecular mechanisms involved in overcoming plant defenses. Here, we show that, through an exceptional horizontal gene transfer event, the whitefly has acquired the plant-derived phenolic glucoside malonyltransferase gene BtPMaT1...
March 22, 2021: Cell
Markus Hoffmann, Prerna Arora, Rüdiger Groß, Alina Seidel, Bojan F Hörnich, Alexander S Hahn, Nadine Krüger, Luise Graichen, Heike Hofmann-Winkler, Amy Kempf, Martin S Winkler, Sebastian Schulz, Hans-Martin Jäck, Bernd Jahrsdörfer, Hubert Schrezenmeier, Martin Müller, Alexander Kleger, Jan Münch, Stefan Pöhlmann
The global spread of SARS-CoV-2/COVID-19 is devastating health systems and economies worldwide. Recombinant or vaccine-induced neutralizing antibodies are used to combat the COVID-19 pandemic. However, the recently emerged SARS-CoV-2 variants B.1.1.7 (UK), B.1.351 (South Africa), and P.1 (Brazil) harbor mutations in the viral spike (S) protein that may alter virus-host cell interactions and confer resistance to inhibitors and antibodies. Here, using pseudoparticles, we show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1, and EK-1-C4...
March 20, 2021: Cell
Makoto Saito, Alim Ladha, Jonathan Strecker, Guilhem Faure, Edwin Neumann, Han Altae-Tran, Rhiannon K Macrae, Feng Zhang
Tn7-like transposons have co-opted CRISPR systems, including class 1 type I-F, I-B, and class 2 type V-K. Intriguingly, although these CRISPR-associated transposases (CASTs) undergo robust CRISPR RNA (crRNA)-guided transposition, they are almost never found in sites targeted by the crRNAs encoded by the cognate CRISPR array. To understand this paradox, we investigated CAST V-K and I-B systems and found two distinct modes of transposition: (1) crRNA-guided transposition and (2) CRISPR array-independent homing...
March 19, 2021: Cell
Silvia Benito-Kwiecinski, Stefano L Giandomenico, Magdalena Sutcliffe, Erlend S Riis, Paula Freire-Pritchett, Iva Kelava, Stephanie Wunderlich, Ulrich Martin, Gregory A Wray, Kate McDole, Madeline A Lancaster
The human brain has undergone rapid expansion since humans diverged from other great apes, but the mechanism of this human-specific enlargement is still unknown. Here, we use cerebral organoids derived from human, gorilla, and chimpanzee cells to study developmental mechanisms driving evolutionary brain expansion. We find that neuroepithelial differentiation is a protracted process in apes, involving a previously unrecognized transition state characterized by a change in cell shape. Furthermore, we show that human organoids are larger due to a delay in this transition, associated with differences in interkinetic nuclear migration and cell cycle length...
March 19, 2021: Cell
Sabina Kaczanowska, Daniel W Beury, Vishaka Gopalan, Arielle K Tycko, Haiying Qin, Miranda E Clements, Justin Drake, Chiadika Nwanze, Meera Murgai, Zachary Rae, Wei Ju, Katherine A Alexander, Jessica Kline, Cristina F Contreras, Kristin M Wessel, Shil Patel, Sridhar Hannenhalli, Michael C Kelly, Rosandra N Kaplan
Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment...
March 19, 2021: Cell
Zhexin Wang, Michael Grange, Thorsten Wagner, Ay Lin Kho, Mathias Gautel, Stefan Raunser
Sarcomeres are force-generating and load-bearing devices of muscles. A precise molecular picture of how sarcomeres are built underpins understanding their role in health and disease. Here, we determine the molecular architecture of native vertebrate skeletal sarcomeres by electron cryo-tomography. Our reconstruction reveals molecular details of the three-dimensional organization and interaction of actin and myosin in the A-band, I-band, and Z-disc and demonstrates that α-actinin cross-links antiparallel actin filaments by forming doublets with 6-nm spacing...
March 19, 2021: Cell
Jacqueline M Fabius, Nevan J Krogan
The scientific world rewards the individual while often discouraging collaboration. However, times of crisis show us how much more we can accomplish when we work together. Here, we describe our approach to breaking down silos and fostering global collaborations and share the lessons we have learned, especially pertaining to research on SARS-CoV-2.
March 18, 2021: Cell
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