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Yan Qin, Brian S Garrison, Wenjiang Ma, Rui Wang, Aiping Jiang, Jing Li, Meeta Mistry, Roderick T Bronson, Daria Santoro, Charlotte Franco, Daisy A Robinton, Beth Stevens, Derrick J Rossi, Chafen Lu, Timothy A Springer
Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33-/- mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months...
June 12, 2018: Cell
Paul K Ziegler, Julia Bollrath, Charles K Pallangyo, Takaji Matsutani, Özge Canli, Tiago De Oliveira, Michaela A Diamanti, Nina Müller, Jaba Gamrekelashvili, Tracy Putoczki, David Horst, Arun K Mankan, Meryem G Öner, Susanna Müller, Josef Müller-Höcker, Thomas Kirchner, Julia Slotta-Huspenina, M Mark Taketo, Thomas Reinheckel, Stefan Dröse, Andrew C Larner, Winfried S Wels, Matthias Ernst, Tim F Greten, Melek C Arkan, Thomas Korn, Dagmar Wirth, Florian R Greten
In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization...
June 11, 2018: Cell
Srinivas R Viswanathan, Gavin Ha, Andreas M Hoff, Jeremiah A Wala, Jian Carrot-Zhang, Christopher W Whelan, Nicholas J Haradhvala, Samuel S Freeman, Sarah C Reed, Justin Rhoades, Paz Polak, Michelle Cipicchio, Stephanie A Wankowicz, Alicia Wong, Tushar Kamath, Zhenwei Zhang, Gregory J Gydush, Denisse Rotem, J Christopher Love, Gad Getz, Stacey Gabriel, Cheng-Zhong Zhang, Scott M Dehm, Peter S Nelson, Eliezer M Van Allen, Atish D Choudhury, Viktor A Adalsteinsson, Rameen Beroukhim, Mary-Ellen Taplin, Matthew Meyerson
Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers...
June 11, 2018: Cell
David Y Takeda, Sándor Spisák, Ji-Heui Seo, Connor Bell, Edward O'Connor, Keegan Korthauer, Dezső Ribli, István Csabai, Norbert Solymosi, Zoltán Szállási, David R Stillman, Paloma Cejas, Xintao Qiu, Henry W Long, Viktória Tisza, Pier Vitale Nuzzo, Mersedeh Rohanizadegan, Mark M Pomerantz, William C Hahn, Matthew L Freedman
Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide...
June 9, 2018: Cell
Nikolaos Konstantinides, Katarina Kapuralin, Chaimaa Fadil, Luendreo Barboza, Rahul Satija, Claude Desplan
Transcription factors regulate the molecular, morphological, and physiological characteristics of neurons and generate their impressive cell-type diversity. To gain insight into the general principles that govern how transcription factors regulate cell-type diversity, we used large-scale single-cell RNA sequencing to characterize the extensive cellular diversity in the Drosophila optic lobes. We sequenced 55,000 single cells and assigned them to 52 clusters. We validated and annotated many clusters using RNA sequencing of FACS-sorted single-cell types and cluster-specific genes...
June 9, 2018: Cell
Kristofer Davie, Jasper Janssens, Duygu Koldere, Maxime De Waegeneer, Uli Pech, Łukasz Kreft, Sara Aibar, Samira Makhzami, Valerie Christiaens, Carmen Bravo González-Blas, Suresh Poovathingal, Gert Hulselmans, Katina I Spanier, Thomas Moerman, Bram Vanspauwen, Sarah Geurs, Thierry Voet, Jeroen Lammertyn, Bernard Thienpont, Sha Liu, Nikos Konstantinides, Mark Fiers, Patrik Verstreken, Stein Aerts
The diversity of cell types and regulatory states in the brain, and how these change during aging, remains largely unknown. We present a single-cell transcriptome atlas of the entire adult Drosophila melanogaster brain sampled across its lifespan. Cell clustering identified 87 initial cell clusters that are further subclustered and validated by targeted cell-sorting. Our data show high granularity and identify a wide range of cell types. Gene network analyses using SCENIC revealed regulatory heterogeneity linked to energy consumption...
June 9, 2018: Cell
Norah L Smith, Ravi K Patel, Arnold Reynaldi, Jennifer K Grenier, Jocelyn Wang, Neva B Watson, Kito Nzingha, Kristel J Yee Mon, Seth A Peng, Andrew Grimson, Miles P Davenport, Brian D Rudd
Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8+ T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge...
June 6, 2018: Cell
Leonardo Almeida-Souza, Rene A W Frank, Javier García-Nafría, Adeline Colussi, Nushan Gunawardana, Christopher M Johnson, Minmin Yu, Gillian Howard, Byron Andrews, Yvonne Vallis, Harvey T McMahon
Multiple proteins act co-operatively in mammalian clathrin-mediated endocytosis (CME) to generate endocytic vesicles from the plasma membrane. The principles controlling the activation and organization of the actin cytoskeleton during mammalian CME are, however, not fully understood. Here, we show that the protein FCHSD2 is a major activator of actin polymerization during CME. FCHSD2 deletion leads to decreased ligand uptake caused by slowed pit maturation. FCHSD2 is recruited to endocytic pits by the scaffold protein intersectin via an unusual SH3-SH3 interaction...
June 4, 2018: Cell
Benjamin Kleaveland, Charlie Y Shi, Joanna Stefano, David P Bartel
Noncoding RNAs (ncRNAs) play increasingly appreciated gene-regulatory roles. Here, we describe a regulatory network centered on four ncRNAs-a long ncRNA, a circular RNA, and two microRNAs-using gene editing in mice to probe the molecular consequences of disrupting key components of this network. The long ncRNA Cyrano uses an extensively paired site to miR-7 to trigger destruction of this microRNA. Cyrano-directed miR-7 degradation is much more effective than previously described examples of target-directed microRNA degradation, which come primarily from studies of artificial and viral RNAs...
June 4, 2018: Cell
Sofia A Quinodoz, Noah Ollikainen, Barbara Tabak, Ali Palla, Jan Marten Schmidt, Elizabeth Detmar, Mason M Lai, Alexander A Shishkin, Prashant Bhat, Yodai Takei, Vickie Trinh, Erik Aznauryan, Pamela Russell, Christine Cheng, Marko Jovanovic, Amy Chow, Long Cai, Patrick McDonel, Manuel Garber, Mitchell Guttman
Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus...
June 4, 2018: Cell
Sheel Shah, Yodai Takei, Wen Zhou, Eric Lubeck, Jina Yun, Chee-Huat Linus Eng, Noushin Koulena, Christopher Cronin, Christoph Karp, Eric J Liaw, Mina Amin, Long Cai
Visualization of the transcriptome and the nuclear organization in situ has been challenging for single-cell analysis. Here, we demonstrate a multiplexed single-molecule in situ method, intron seqFISH, that allows imaging of 10,421 genes at their nascent transcription active sites in single cells, followed by mRNA and lncRNA seqFISH and immunofluorescence. This nascent transcriptome-profiling method can identify different cell types and states with mouse embryonic stem cells and fibroblasts. The nascent sites of RNA synthesis tend to be localized on the surfaces of chromosome territories, and their organization in individual cells is highly variable...
May 31, 2018: Cell
Diogo M Camacho, Katherine M Collins, Rani K Powers, James C Costello, James J Collins
Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology...
May 31, 2018: Cell
Jin Young Kang, Rachel Anne Mooney, Yuri Nedialkov, Jason Saba, Tatiana V Mishanina, Irina Artsimovitch, Robert Landick, Seth A Darst
NusG/RfaH/Spt5 transcription elongation factors are the only transcription regulators conserved across all life. Bacterial NusG regulates RNA polymerase (RNAP) elongation complexes (ECs) across most genes, enhancing elongation by suppressing RNAP backtracking and coordinating ρ-dependent termination and translation. The NusG paralog RfaH engages the EC only at operon polarity suppressor (ops) sites and suppresses both backtrack and hairpin-stabilized pausing. We used single-particle cryoelectron microscopy (cryo-EM) to determine structures of ECs at ops with NusG or RfaH...
May 30, 2018: Cell
Chen-Yu Wang, Teddy Jégu, Hsueh-Ping Chu, Hyun Jung Oh, Jeannie T Lee
Mammalian chromosomes are partitioned into A/B compartments and topologically associated domains (TADs). The inactive X (Xi) chromosome, however, adopts a distinct conformation without evident compartments or TADs. Here, through exploration of an architectural protein, structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1), we probe how the Xi is reconfigured during X chromosome inactivation. A/B compartments are first fused into "S1" and "S2" compartments, coinciding with Xist spreading into gene-rich domains...
May 28, 2018: Cell
Chaoran Li, Joanna R DiSpirito, David Zemmour, Raul German Spallanzani, Wilson Kuswanto, Christophe Benoist, Diane Mathis
Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario...
May 24, 2018: Cell
Christoph Schneider, Claire E O'Leary, Jakob von Moltke, Hong-Erh Liang, Qi Yan Ang, Peter J Turnbaugh, Sridhar Radhakrishnan, Michael Pellizzon, Averil Ma, Richard M Locksley
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome...
May 23, 2018: Cell
Zandra E Walton, Chirag H Patel, Rebekah C Brooks, Yongjun Yu, Arig Ibrahim-Hashim, Malini Riddle, Alessandra Porcu, Tianying Jiang, Brett L Ecker, Feven Tameire, Constantinos Koumenis, Ashani T Weeraratna, David K Welsh, Robert Gillies, James C Alwine, Lin Zhang, Jonathan D Powell, Chi V Dang
Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status...
May 23, 2018: Cell
Suvi Jain, Zhaoqing Ba, Yu Zhang, Hai-Qiang Dai, Frederick W Alt
RAG endonuclease initiates antibody heavy chain variable region exon assembly from V, D, and J segments within a chromosomal V(D)J recombination center (RC) by cleaving between paired gene segments and flanking recombination signal sequences (RSSs). The IGCR1 control region promotes DJH intermediate formation by isolating Ds, JH s, and RCs from upstream VH s in a chromatin loop anchored by CTCF-binding elements (CBEs). How VH s access the DJH RC for VH to DJH rearrangement was unknown. We report that CBEs immediately downstream of frequently rearranged VH -RSSs increase recombination potential of their associated VH far beyond that provided by RSSs alone...
May 18, 2018: Cell
Lu Chen, Caitlin M Roake, Adam Freund, Pedro J Batista, Siqi Tian, Yi A Yin, Chandresh R Gajera, Shengda Lin, Byron Lee, Matthew F Pech, Andrew S Venteicher, Rhiju Das, Howard Y Chang, Steven E Artandi
Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains-a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly...
May 18, 2018: Cell
Adar Adamsky, Adi Kol, Tirzah Kreisel, Adi Doron, Nofar Ozeri-Engelhard, Talia Melcer, Ron Refaeli, Henrike Horn, Limor Regev, Maya Groysman, Michael London, Inbal Goshen
Astrocytes respond to neuronal activity and were shown to be necessary for plasticity and memory. To test whether astrocytic activity is also sufficient to generate synaptic potentiation and enhance memory, we expressed the Gq-coupled receptor hM3Dq in CA1 astrocytes, allowing their activation by a designer drug. We discovered that astrocytic activation is not only necessary for synaptic plasticity, but also sufficient to induce NMDA-dependent de novo long-term potentiation in the hippocampus that persisted after astrocytic activation ceased...
May 18, 2018: Cell
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