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https://www.readbyqxmd.com/read/29224780/a-living-biobank-of-breast-cancer-organoids-captures-disease-heterogeneity
#1
Norman Sachs, Joep de Ligt, Oded Kopper, Ewa Gogola, Gergana Bounova, Fleur Weeber, Anjali Vanita Balgobind, Karin Wind, Ana Gracanin, Harry Begthel, Jeroen Korving, Ruben van Boxtel, Alexandra Alves Duarte, Daphne Lelieveld, Arne van Hoeck, Robert Frans Ernst, Francis Blokzijl, Isaac Johannes Nijman, Marlous Hoogstraat, Marieke van de Ven, David Anthony Egan, Vittoria Zinzalla, Jurgen Moll, Sylvia Fernandez Boj, Emile Eugene Voest, Lodewyk Wessels, Paul Joannes van Diest, Sven Rottenberg, Robert Gerhardus Jacob Vries, Edwin Cuppen, Hans Clevers
Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging...
December 5, 2017: Cell
https://www.readbyqxmd.com/read/29224783/in%C3%A2-vivo-target-gene-activation-via-crispr-cas9-mediated-trans-epigenetic-modulation
#2
Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D O'Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29224782/mfd-dynamically-regulates-transcription-via-a-release-and-catch-up-mechanism
#3
Tung T Le, Yi Yang, Chuang Tan, Margaret M Suhanovsky, Robert M Fulbright, James T Inman, Ming Li, Jaeyoon Lee, Sarah Perelman, Jeffrey W Roberts, Alexandra M Deaconescu, Michelle D Wang
The bacterial Mfd ATPase is increasingly recognized as a general transcription factor that participates in the resolution of transcription conflicts with other processes/roadblocks. This function stems from Mfd's ability to preferentially act on stalled RNA polymerases (RNAPs). However, the mechanism underlying this preference and the subsequent coordination between Mfd and RNAP have remained elusive. Here, using a novel real-time translocase assay, we unexpectedly discovered that Mfd translocates autonomously on DNA...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29224781/structural-basis-for-regulated-proteolysis-by-the-%C3%AE-secretase-adam10
#4
Tom C M Seegar, Lauren B Killingsworth, Nayanendu Saha, Peter A Meyer, Dhabaleswar Patra, Brandon Zimmerman, Peter W Janes, Eric Rubinstein, Dimitar B Nikolov, Georgios Skiniotis, Andrew C Kruse, Stephen C Blacklow
Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29224777/yy1-is-a-structural-regulator-of-enhancer-promoter-loops
#5
Abraham S Weintraub, Charles H Li, Alicia V Zamudio, Alla A Sigova, Nancy M Hannett, Daniel S Day, Brian J Abraham, Malkiel A Cohen, Behnam Nabet, Dennis L Buckley, Yang Eric Guo, Denes Hnisz, Rudolf Jaenisch, James E Bradner, Nathanael S Gray, Richard A Young
There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29198525/a-j-protein-co-chaperone-recruits-bip-to-monomerize-ire1-and-repress-the-unfolded-protein-response
#6
Niko Amin-Wetzel, Reuben A Saunders, Maarten J Kamphuis, Claudia Rato, Steffen Preissler, Heather P Harding, David Ron
When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD)...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29198524/single-cell-transcriptomic-analysis-of-primary-and-metastatic-tumor-ecosystems-in-head-and-neck-cancer
#7
Sidharth V Puram, Itay Tirosh, Anuraag S Parikh, Anoop P Patel, Keren Yizhak, Shawn Gillespie, Christopher Rodman, Christina L Luo, Edmund A Mroz, Kevin S Emerick, Daniel G Deschler, Mark A Varvares, Ravi Mylvaganam, Orit Rozenblatt-Rosen, James W Rocco, William C Faquin, Derrick T Lin, Aviv Regev, Bradley E Bernstein
The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT)...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29224779/combined-social-and-spatial-coding-in-a-descending-projection-from-the-prefrontal-cortex
#8
Malavika Murugan, Hee Jae Jang, Michelle Park, Ellia M Miller, Julia Cox, Joshua P Taliaferro, Nathan F Parker, Varun Bhave, Hong Hur, Yupu Liang, Alexander R Nectow, Jonathan W Pillow, Ilana B Witten
Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target...
November 22, 2017: Cell
https://www.readbyqxmd.com/read/29198526/neuromodulatory-control-of-long-term-behavioral-patterns-and-individuality-across-development
#9
Shay Stern, Christoph Kirst, Cornelia I Bargmann
Animals generate complex patterns of behavior across development that may be shared or unique to individuals. Here, we examine the contributions of developmental programs and individual variation to behavior by monitoring single Caenorhabditis elegans nematodes over their complete developmental trajectories and quantifying their behavior at high spatiotemporal resolution. These measurements reveal reproducible trajectories of spontaneous foraging behaviors that are stereotyped within and between developmental stages...
November 21, 2017: Cell
https://www.readbyqxmd.com/read/29224778/rapid-mobilization-reveals-a-highly-engraftable-hematopoietic-stem-cell
#10
Jonathan Hoggatt, Pratibha Singh, Tiffany A Tate, Bin-Kuan Chou, Shruti R Datari, Seiji Fukuda, Liqiong Liu, Peter V Kharchenko, Amir Schajnovitz, Ninib Baryawno, Francois E Mercier, Joseph Boyer, Jason Gardner, Dwight M Morrow, David T Scadden, Louis M Pelus
Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF)...
November 17, 2017: Cell
https://www.readbyqxmd.com/read/29153834/precise-editing-at-dna-replication-forks-enables-multiplex-genome-engineering-in-eukaryotes
#11
Edward M Barbieri, Paul Muir, Benjamin O Akhuetie-Oni, Christopher M Yellman, Farren J Isaacs
We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation...
November 15, 2017: Cell
https://www.readbyqxmd.com/read/29153836/post-transcriptional-regulation-of-de-novo-lipogenesis-by-mtorc1-s6k1-srpk2-signaling
#12
Gina Lee, Yuxiang Zheng, Sungyun Cho, Cholsoon Jang, Christina England, Jamie M Dempsey, Yonghao Yu, Xiaolei Liu, Long He, Paola M Cavaliere, Andre Chavez, Erik Zhang, Meltem Isik, Anthony Couvillon, Noah E Dephoure, T Keith Blackwell, Jane J Yu, Joshua D Rabinowitz, Lewis C Cantley, John Blenis
mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling...
November 14, 2017: Cell
https://www.readbyqxmd.com/read/29153837/a-method-for-the-acute-and-rapid-degradation-of-endogenous-proteins
#13
Dean Clift, William A McEwan, Larisa I Labzin, Vera Konieczny, Binyam Mogessie, Leo C James, Melina Schuh
Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA...
November 13, 2017: Cell
https://www.readbyqxmd.com/read/29153835/efficient-generation-of-transcriptomic-profiles-by-random-composite-measurements
#14
Brian Cleary, Le Cong, Anthea Cheung, Eric S Lander, Aviv Regev
RNA profiles are an informative phenotype of cellular and tissue states but can be costly to generate at massive scale. Here, we describe how gene expression levels can be efficiently acquired with random composite measurements-in which abundances are combined in a random weighted sum. We show (1) that the similarity between pairs of expression profiles can be approximated with very few composite measurements; (2) that by leveraging sparse, modular representations of gene expression, we can use random composite measurements to recover high-dimensional gene expression levels (with 100 times fewer measurements than genes); and (3) that it is possible to blindly recover gene expression from composite measurements, even without access to training data...
November 13, 2017: Cell
https://www.readbyqxmd.com/read/29153832/drastic-genome-reduction-in-an-herbivore-s-pectinolytic-symbiont
#15
Hassan Salem, Eugen Bauer, Roy Kirsch, Aileen Berasategui, Michael Cripps, Benjamin Weiss, Ryuichi Koga, Kayoko Fukumori, Heiko Vogel, Takema Fukatsu, Martin Kaltenpoth
Pectin, an integral component of the plant cell wall, is a recalcitrant substrate against enzymatic challenges by most animals. In characterizing the source of a leaf beetle's (Cassida rubiginosa) pectin-degrading phenotype, we demonstrate its dependency on an extracellular bacterium housed in specialized organs connected to the foregut. Despite possessing the smallest genome (0.27 Mb) of any organism not subsisting within a host cell, the symbiont nonetheless retained a functional pectinolytic metabolism targeting the polysaccharide's two most abundant classes: homogalacturonan and rhamnogalacturonan I...
November 10, 2017: Cell
https://www.readbyqxmd.com/read/29198523/resetting-the-yeast-epigenome-with-human-nucleosomes
#16
David M Truong, Jef D Boeke
Humans and yeast are separated by a billion years of evolution, yet their conserved histones retain central roles in gene regulation. Here, we "reset" yeast to use core human nucleosomes in lieu of their own (a rare event taking 20 days), which initially only worked with variant H3.1. The cells adapt by acquiring suppressor mutations in cell-division genes or by acquiring certain aneuploid states. Converting five histone residues to their yeast counterparts restored robust growth. We reveal that humanized nucleosomes are positioned according to endogenous yeast DNA sequence and chromatin-remodeling network, as judged by a yeast-like nucleosome repeat length...
November 8, 2017: Cell
https://www.readbyqxmd.com/read/29129375/light-controls-protein-localization-through-phytochrome-mediated-alternative-promoter-selection
#17
Tomokazu Ushijima, Kousuke Hanada, Eiji Gotoh, Wataru Yamori, Yutaka Kodama, Hiroyuki Tanaka, Miyako Kusano, Atsushi Fukushima, Mutsutomo Tokizawa, Yoshiharu Y Yamamoto, Yasuomi Tada, Yutaka Suzuki, Tomonao Matsushita
Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The impact of this mechanism on the proteome and whether it is positively exploited in normal organismal responses remain unclear. We found that the plant photoreceptor phytochrome induces genome-wide changes in alternative promoter selection in Arabidopsis thaliana. Through this mechanism, protein isoforms with different N termini are produced that display light-dependent differences in localization...
November 7, 2017: Cell
https://www.readbyqxmd.com/read/29153833/structure-of-the-post-catalytic-spliceosome-from-saccharomyces-cerevisiae
#18
Rui Bai, Chuangye Yan, Ruixue Wan, Jianlin Lei, Yigong Shi
Removal of an intron from a pre-mRNA by the spliceosome results in the ligation of two exons in the post-catalytic spliceosome (known as the P complex). Here, we present a cryo-EM structure of the P complex from Saccharomyces cerevisiae at an average resolution of 3.6 Å. The ligated exon is held in the active site through RNA-RNA contacts. Three bases at the 3' end of the 5' exon remain anchored to loop I of U5 small nuclear RNA, and the conserved AG nucleotides of the 3'-splice site (3'SS) are specifically recognized by the invariant adenine of the branch point sequence, the guanine base at the 5' end of the 5'SS, and an adenine base of U6 snRNA...
November 4, 2017: Cell
https://www.readbyqxmd.com/read/29129376/lysophosphatidylcholine-regulates-sexual-stage-differentiation-in-the-human-malaria-parasite-plasmodium-falciparum
#19
Nicolas M B Brancucci, Joseph P Gerdt, ChengQi Wang, Mariana De Niz, Nisha Philip, Swamy R Adapa, Min Zhang, Eva Hitz, Igor Niederwieser, Sylwia D Boltryk, Marie-Claude Laffitte, Martha A Clark, Christof Grüring, Deepali Ravel, Alexandra Blancke Soares, Allison Demas, Selina Bopp, Belén Rubio-Ruiz, Ana Conejo-Garcia, Dyann F Wirth, Edyta Gendaszewska-Darmach, Manoj T Duraisingh, John H Adams, Till S Voss, Andrew P Waters, Rays H Y Jiang, Jon Clardy, Matthias Marti
Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation...
November 2, 2017: Cell
https://www.readbyqxmd.com/read/29103613/ancestral-circuits-for-the-coordinated-modulation-of-brain-state
#20
Matthew Lovett-Barron, Aaron S Andalman, William E Allen, Sam Vesuna, Isaac Kauvar, Vanessa M Burns, Karl Deisseroth
Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness...
November 2, 2017: Cell
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