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1. A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

Author:
El Khattabi, Laila; Zhao, Haiyan; Kalchschmidt, Jens; Young, Natalie; Jung, Seolkyoung; Van Blerkom, Peter; Kieffer-Kwon, Philippe; Kieffer-Kwon, Kyong-Rim; Park, Solji; Wang, Xiang; Krebs, Jordan; Tripathi, Subhash; Sakabe, Noboru; Sobreira, Débora R.; Huang, Su-Chen; Rao, Suhas S.P.; Pruett, Nathanael; Chauss, Daniel; Sadler, Erica; Lopez, Andrea; Nóbrega, Marcelo A.; Aiden, Erez Lieberman; Asturias, Francisco J.; Casellas, Rafael
Source:
Cell 2019 v.178 no.5 pp. 1145-1158.e20
ISSN:
0092-8674
Subject:
CRISPR-Cas systems; DNA; cryo-electron microscopy; embryonic stem cells; enzymes; mammals; mechanism of action; models; topology; transcription factors
Abstract:
... While Mediator plays a key role in eukaryotic transcription, little is known about its mechanism of action. This study combines CRISPR-Cas9 genetic screens, degron assays, Hi-C, and cryoelectron microscopy (cryo-EM) to dissect the function and structure of mammalian Mediator (mMED). Deletion analyses in B, T, and embryonic stem cells (ESC) identified a core of essential subunits required for Pol I ...
DOI:
10.1016/j.cell.2019.07.011

2. A Species-Wide Inventory of NLR Genes and Alleles in Arabidopsis thaliana

Author:
Van de Weyer, Anna-Lena; Monteiro, Freddy; Furzer, Oliver J.; Nishimura, Marc T.; Cevik, Volkan; Witek, Kamil; Jones, Jonathan D.G.; Dangl, Jeffery L.; Weigel, Detlef; Bemm, Felix
Source:
Cell 2019 v.178 no.5 pp. 1260-1272.e14
ISSN:
0092-8674
Subject:
Arabidopsis thaliana; alleles; disease resistance; immunologic receptors; infectious diseases; inventories; pathogens
Abstract:
... Infectious disease is both a major force of selection in nature and a prime cause of yield loss in agriculture. In plants, disease resistance is often conferred by nucleotide-binding leucine-rich repeat (NLR) proteins, intracellular immune receptors that recognize pathogen proteins and their effects on the host. Consistent with extensive balancing and positive selection, NLRs are encoded by one of ...
DOI:
10.1016/j.cell.2019.07.038
PubMed:
31442410
PubMed Central:
PMC6709784

3. Dietary Intake Regulates the Circulating Inflammatory Monocyte Pool

Author:
Jordan, Stefan; Tung, Navpreet; Casanova-Acebes, Maria; Chang, Christie; Cantoni, Claudia; Zhang, Dachuan; Wirtz, Theresa H.; Naik, Shruti; Rose, Samuel A.; Brocker, Chad N.; Gainullina, Anastasiia; Hornburg, Daniel; Horng, Sam; Maier, Barbara B.; Cravedi, Paolo; LeRoith, Derek; Gonzalez, Frank J.; Meissner, Felix; Ochando, Jordi; Rahman, Adeeb; Chipuk, Jerry E.; Artyomov, Maxim N.; Frenette, Paul S.; Piccio, Laura; Berres, Marie-Luise; Gallagher, Emily J.; Merad, Miriam
Source:
Cell 2019 v.178 no.5 pp. 1102-1114.e17
ISSN:
0092-8674
Subject:
autoimmune diseases; bone marrow; chemokine CCL2; energy intake; fasting; food intake; glucose; hepatocytes; inflammation; liver; low calorie diet; monocytes; peroxisome proliferator-activated receptor alpha; protein content; protein kinases; tissue repair
Abstract:
... Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary gl ...
DOI:
10.1016/j.cell.2019.07.050

4. Dipeptidase-1 Is an Adhesion Receptor for Neutrophil Recruitment in Lungs and Liver

Author:
Choudhury, Saurav Roy; Babes, Liane; Rahn, Jennifer J.; Ahn, Bo-Young; Goring, Kimberly-Ann R.; King, Jennifer C.; Lau, Arthur; Petri, Björn; Hao, Xiaoguang; Chojnacki, Andrew K.; Thanabalasuriar, Ajitha; McAvoy, Erin F.; Tabariès, Sébastien; Schraeder, Christoph; Patel, Kamala D.; Siegel, Peter M.; Kopciuk, Karen A.; Schriemer, David C.; Muruve, Daniel A.; Kelly, Margaret M.; Yipp, Bryan G.; Kubes, Paul; Robbins, Stephen M.; Senger, Donna L.
Source:
Cell 2019 v.178 no.5 pp. 1205-1221.e17
ISSN:
0092-8674
Subject:
adhesion; blood flow; endothelium; endotoxemia; enzyme activity; image analysis; in vitro culture; inflammation; integrins; liver; lungs; neutrophils; peptides; therapeutics
Abstract:
... A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these ...
DOI:
10.1016/j.cell.2019.07.017

5. Effector TH17 Cells Give Rise to Long-Lived TRM Cells that Are Essential for an Immediate Response against Bacterial Infection

Author:
Amezcua Vesely, Maria Carolina; Pallis, Paris; Bielecki, Piotr; Low, Jun Siong; Zhao, Jun; Harman, Christian C.D.; Kroehling, Lina; Jackson, Ruaidhrí; Bailis, Will; Licona-Limón, Paula; Xu, Hao; Iijima, Norifumi; Pillai, Padmini S.; Kaplan, Daniel H.; Weaver, Casey T.; Kluger, Yuval; Kowalczyk, Monika S.; Iwasaki, Akiko; Pereira, Joao P.; Esplugues, Enric; Gagliani, Nicola; Flavell, Richard A.
Source:
Cell 2019 v.178 no.5 pp. 1176-1188.e15
ISSN:
0092-8674
Subject:
Klebsiella pneumoniae; T-lymphocytes; adaptive immunity; animal models; antibodies; bacterial infections; endothelial cells; immunization; interleukin-17; interleukin-7; lungs; mice; vaccine development
Abstract:
... Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (TRM) cells. However, the cellular origin of CD4 TRM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 TRM cells derive from IL-17A-producing ef ...
DOI:
10.1016/j.cell.2019.07.032
PubMed:
31442406
PubMed Central:
PMC7057720

6. Fasting-Refeeding Impacts Immune Cell Dynamics and Mucosal Immune Responses

Author:
Nagai, Motoyoshi; Noguchi, Ryotaro; Takahashi, Daisuke; Morikawa, Takayuki; Koshida, Kouhei; Komiyama, Seiga; Ishihara, Narumi; Yamada, Takahiro; Kawamura, Yuki I.; Muroi, Kisara; Hattori, Kouya; Kobayashi, Nobuhide; Fujimura, Yumiko; Hirota, Masato; Matsumoto, Ryohtaroh; Aoki, Ryo; Tamura-Nakano, Miwa; Sugiyama, Machiko; Katakai, Tomoya; Sato, Shintaro; Takubo, Keiyo; Dohi, Taeko; Hase, Koji
Source:
Cell 2019 v.178 no.5 pp. 1072-1087.e14
ISSN:
0092-8674
Subject:
B-lymphocytes; Peyer's patches; apoptosis; bone marrow; chemokine CXCL13; diarrhea; digestive system; fasting; homeostasis; immune response; immunoglobulin A; lymph nodes; mucosal immunity; nutritional status; oral vaccination; ovalbumin; refeeding; stromal cells
Abstract:
... Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by ∼50% in Peyer’s patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose ...
DOI:
10.1016/j.cell.2019.07.047

7. GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance

Author:
Luan, Harding H.; Wang, Andrew; Hilliard, Brandon K.; Carvalho, Fernando; Rosen, Connor E.; Ahasic, Amy M.; Herzog, Erica L.; Kang, Insoo; Pisani, Margaret A.; Yu, Shuang; Zhang, Cuiling; Ring, Aaron M.; Young, Lawrence H.; Medzhitov, Ruslan
Source:
Cell 2019 v.178 no.5 pp. 1231-1244.e11
ISSN:
0092-8674
Subject:
body temperature; cardiac output; disease resistance; inflammation; lipid metabolism; pathogens; protective effect; sepsis (infection); triacylglycerols
Abstract:
... Growth and differentiation factor 15 (GDF15) is an inflammation-associated hormone with poorly defined biology. Here, we investigated the role of GDF15 in bacterial and viral infections. We found that inflammation induced GDF15, and that GDF15 was necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen con ...
DOI:
10.1016/j.cell.2019.07.033
PubMed:
31402172
PubMed Central:
PMC6863354

8. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet

Author:
Cheng, Chia-Wei; Biton, Moshe; Haber, Adam L.; Gunduz, Nuray; Eng, George; Gaynor, Liam T.; Tripathi, Surya; Calibasi-Kocal, Gizem; Rickelt, Steffen; Butty, Vincent L.; Moreno-Serrano, Marta; Iqbal, Ameena M.; Bauer-Rowe, Khristian E.; Imada, Shinya; Ulutas, Mehmet Sefa; Mylonas, Constantine; Whary, Mark T.; Levine, Stuart S.; Basbinar, Yasemin; Hynes, Richard O.; Mino-Kenudson, Mari; Deshpande, Vikram; Boyer, Laurie A.; Fox, James G.; Terranova, Christopher; Rai, Kunal; Piwnica-Worms, Helen; Mihaylova, Maria M.; Regev, Aviv; Yilmaz, Ömer H.
Source:
Cell 2019 v.178 no.5 pp. 1115-1131.e15
ISSN:
0092-8674
Subject:
3-hydroxybutyric acid; genes; histone deacetylase; homeostasis; hydroxymethylglutaryl-CoA synthase; ketogenic diet; ketone bodies; mammals; small intestine; stem cells
Abstract:
... Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from dif ...
DOI:
10.1016/j.cell.2019.07.048
PubMed:
31442404
PubMed Central:
PMC6732196

9. Large-Scale Analyses of Human Microbiomes Reveal Thousands of Small, Novel Genes

Author:
Sberro, Hila; Fremin, Brayon J.; Zlitni, Soumaya; Edfors, Fredrik; Greenfield, Nicholas; Snyder, Michael P.; Pavlopoulos, Georgios A.; Kyrpides, Nikos C.; Bhatt, Ami S.
Source:
Cell 2019 v.178 no.5 pp. 1245-1259.e14
ISSN:
0092-8674
Subject:
genes; metagenomics; microbiome; proteins; translation (genetics)
Abstract:
... Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe >4,000 conserved protein families, the majority of which are novel; ∼30% of these protein families are predicted to b ...
DOI:
10.1016/j.cell.2019.07.016
PubMed:
31402174
PubMed Central:
PMC6764417

10. Loss of Ataxin-1 Potentiates Alzheimer’s Pathogenesis by Elevating Cerebral BACE1 Transcription

Author:
Suh, Jaehong; Romano, Donna M.; Nitschke, Larissa; Herrick, Scott P.; DiMarzio, Britt A.; Dzhala, Volodymyr; Bae, Jun-Seok; Oram, Mary K.; Zheng, Yuejiao; Hooli, Basavaraj; Mullin, Kristina; Gennarino, Vincenzo A.; Wasco, Wilma; Schmahmann, Jeremy D.; Albers, Mark W.; Zoghbi, Huda Y.; Tanzi, Rudolph E.
Source:
Cell 2019 v.178 no.5 pp. 1159-1175.e17
ISSN:
0092-8674
Subject:
Alzheimer disease; animal models; ataxia (disorder); cerebellum; cerebrum; cognition; mice; microsatellite repeats; mutants; neurodegenerative diseases; neurogenesis; pathogenesis; patients; risk factors
Abstract:
... Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer’s disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC ...
DOI:
10.1016/j.cell.2019.07.043
PubMed:
31442405
PubMed Central:
PMC6726125

11. Mammalian Mediator as a Functional Link between Enhancers and Promoters

Author:
Soutourina, Julie
Source:
Cell 2019 v.178 no.5 pp. 1036-1038
ISSN:
0092-8674
Subject:
genomics; mammals; mechanism of action; transcription (genetics)
Abstract:
... In this issue of Cell, Casellas and colleagues provide insights into the structural and functional aspects of the mammalian multi-subunit Mediator complex, a conserved and essential transcriptional coregulator. Combining cryo-EM, genetic, and genomic analyses, the work sheds light on Mediator’s mode of action as a functional bridge between enhancers and promoters. ...
DOI:
10.1016/j.cell.2019.07.040

12. Molecular Strategies of Meiotic Cheating by Selfish Centromeres

Author:
Akera, Takashi; Trimm, Emily; Lampson, Michael A.
Source:
Cell 2019 v.178 no.5 pp. 1132-1144.e10
ISSN:
0092-8674
Subject:
DNA; animal models; centromeres; eggs; females; histones; meiosis; mice; microtubules; phosphorylation
Abstract:
... Asymmetric division in female meiosis creates selective pressure favoring selfish centromeres that bias their transmission to the egg. This centromere drive can explain the paradoxical rapid evolution of both centromere DNA and centromere-binding proteins despite conserved centromere function. Here, we define a molecular pathway linking expanded centromeres to histone phosphorylation and recruitme ...
DOI:
10.1016/j.cell.2019.07.001
PubMed:
31402175
PubMed Central:
PMC6731994

13. Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7

Author:
Jaeger, Kathrin; Bruenle, Steffen; Weinert, Tobias; Guba, Wolfgang; Muehle, Jonas; Miyazaki, Takuya; Weber, Martin; Furrer, Antonia; Haenggi, Noemi; Tetaz, Tim; Huang, Chia-Ying; Mattle, Daniel; Vonach, Jean-Marie; Gast, Alain; Kuglstatter, Andreas; Rudolph, Markus G.; Nogly, Przemyslaw; Benz, Joerg; Dawson, Roger J.P.; Standfuss, Joerg
Source:
Cell 2019 v.178 no.5 pp. 1222-1230.e10
ISSN:
0092-8674
Subject:
CCR7 receptor; antagonists; automation; crystal structure; immunity; ligands; lymph nodes; metastasis; neoplasms; protein binding; screening; sialidase; therapeutics; thermal stability
Abstract:
... The CC chemokine receptor 7 (CCR7) balances immunity and tolerance by homeostatic trafficking of immune cells. In cancer, CCR7-mediated trafficking leads to lymph node metastasis, suggesting the receptor as a promising therapeutic target. Here, we present the crystal structure of human CCR7 fused to the protein Sialidase NanA by using data up to 2.1 Å resolution. The structure shows the ligand Cmp ...
DOI:
10.1016/j.cell.2019.07.028
PubMed:
31442409
PubMed Central:
PMC6709783

14. Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells

Author:
Dong, Matthew B.; Wang, Guangchuan; Chow, Ryan D.; Ye, Lupeng; Zhu, Lvyun; Dai, Xiaoyun; Park, Jonathan J.; Kim, Hyunu R.; Errami, Youssef; Guzman, Christopher D.; Zhou, Xiaoyu; Chen, Krista Y.; Renauer, Paul A.; Du, Yaying; Shen, Johanna; Lam, Stanley Z.; Zhou, Jingjia J.; Lannin, Donald R.; Herbst, Roy S.; Chen, Sidi
Source:
Cell 2019 v.178 no.5 pp. 1189-1204.e23
ISSN:
0092-8674
Subject:
CD8-positive T-lymphocytes; RNA helicases; breast neoplasms; cytokines; gene editing; genes; immune response; immunotherapy; mice; transcription factor NF-kappa B; transcriptomics
Abstract:
... CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. T ...
DOI:
10.1016/j.cell.2019.07.044
PubMed:
31442407
PubMed Central:
PMC6719679

15. The Bone Marrow Protects and Optimizes Immunological Memory during Dietary Restriction

Author:
Collins, Nicholas; Han, Seong-Ji; Enamorado, Michel; Link, Verena M.; Huang, Bonnie; Moseman, E. Ashley; Kishton, Rigel J.; Shannon, John P.; Dixit, Dhaval; Schwab, Susan R.; Hickman, Heather D.; Restifo, Nicholas P.; McGavern, Dorian B.; Schwartzberg, Pamela L.; Belkaid, Yasmine
Source:
Cell 2019 v.178 no.5 pp. 1088-1101.e15
ISSN:
0092-8674
Subject:
T-lymphocytes; adipocytes; adipogenesis; bone marrow; dietary restriction; energy conservation; erythropoiesis; food availability; glucocorticoids; immunologic memory; lymphatic system; malnutrition; mammals; neoplasms
Abstract:
... Mammals evolved in the face of fluctuating food availability. How the immune system adapts to transient nutritional stress remains poorly understood. Here, we show that memory T cells collapsed in secondary lymphoid organs in the context of dietary restriction (DR) but dramatically accumulated within the bone marrow (BM), where they adopted a state associated with energy conservation. This respons ...
DOI:
10.1016/j.cell.2019.07.049
PubMed:
31442402
PubMed Central:
PMC6818271

16. Therapeutic Opportunities in Inflammatory Bowel Disease: Mechanistic Dissection of Host-Microbiome Relationships

Author:
Plichta, Damian R.; Graham, Daniel B.; Subramanian, Sathish; Xavier, Ramnik J.
Source:
Cell 2019 v.178 no.5 pp. 1041-1056
ISSN:
0092-8674
Subject:
environmental exposure; genetic factors; homeostasis; immunity; inflammation; inflammatory bowel disease; intestines; metabolites; microbiome; microorganisms; pathogenesis; therapeutics
Abstract:
... The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions be ...
DOI:
10.1016/j.cell.2019.07.045
PubMed:
31442399
PubMed Central:
PMC6778965

17. Tiny Hidden Genes within Our Microbiome

Author:
Mittelman, Karin; Burstein, David
Source:
Cell 2019 v.178 no.5 pp. 1034-1035
ISSN:
0092-8674
Subject:
bacteria; genes; hosts; microbiome; proteins
Abstract:
... Exploration of tiny protein-coding sequences within the human microbiome reveals thousands of conserved gene families that have been overlooked by traditional analyses. These small proteins may play key roles in the crosstalk among bacteria within the microbiome and in interactions with their human hosts. ...
DOI:
10.1016/j.cell.2019.07.039

18. Travel Surveillance and Genomics Uncover a Hidden Zika Outbreak during the Waning Epidemic

Author:
Grubaugh, Nathan D.; Saraf, Sharada; Gangavarapu, Karthik; Watts, Alexander; Tan, Amanda L.; Oidtman, Rachel J.; Ladner, Jason T.; Oliveira, Glenn; Matteson, Nathaniel L.; Kraemer, Moritz U.G.; Vogels, Chantal B.F.; Hentoff, Aaron; Bhatia, Deepit; Stanek, Danielle; Scott, Blake; Landis, Vanessa; Stryker, Ian; Cone, Marshall R.; Kopp, Edgar W.; Cannons, Andrew C.; Heberlein-Larson, Lea; White, Stephen; Gillis, Leah D.; Ricciardi, Michael J.; Kwal, Jaclyn; Lichtenberger, Paola K.; Magnani, Diogo M.; Watkins, David I.; Palacios, Gustavo; Hamer, Davidson H.; Gardner, Lauren M.; Perkins, T. Alex; Baele, Guy; Khan, Kamran; Morrison, Andrea; Isern, Sharon; Michael, Scott F.; Andersen, Kristian G.
Source:
Cell 2019 v.178 no.5 pp. 1057-1071.e11
ISSN:
0092-8674
Subject:
Zika virus; genomics; islands; monitoring; mosquito control; travel; virus transmission; viruses; Caribbean; Cuba; North America; South America
Abstract:
... The Zika epidemic in the Americas has challenged surveillance and control. As the epidemic appears to be waning, it is unclear whether transmission is still ongoing, which is exacerbated by discrepancies in reporting. To uncover locations with lingering outbreaks, we investigated travel-associated Zika cases to identify transmission not captured by reporting. We uncovered an unreported outbreak in ...
DOI:
10.1016/j.cell.2019.07.018
PubMed:
31442400
PubMed Central:
PMC6716374

19. When Fasting Gets Tough, the Tough Immune Cells Get Going—or Die

Author:
Buono, Roberta; Longo, Valter D.
Source:
Cell 2019 v.178 no.5 pp. 1038-1040
ISSN:
0092-8674
Subject:
autoimmunity; fasting; low calorie diet; neoplasm cells; neoplasms
Abstract:
... Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells, but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the drastic and complex effects of fasting and severe calorie restriction on the levels and localization of different immune cells and the mechanisms responsible for them. ...
DOI:
10.1016/j.cell.2019.07.052