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Genes & Development

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https://www.readbyqxmd.com/read/28924035/stat1-modulates-tissue-wasting-or-overgrowth-downstream-from-pdgfr%C3%AE
#1
Chaoyong He, Shayna C Medley, Jang Kim, Chengyi Sun, Hae Ryong Kwon, Hiromi Sakashita, Yair Pincu, Longbiao Yao, Danielle Eppard, Bojie Dai, William L Berry, Timothy M Griffin, Lorin E Olson
Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb(+/D849V) mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype...
September 18, 2017: Genes & Development
https://www.readbyqxmd.com/read/28924034/polycomb-directs-timely-activation-of-germline-genes-in-spermatogenesis
#2
So Maezawa, Kazuteru Hasegawa, Masashi Yukawa, Akihiko Sakashita, Kris G Alavattam, Paul R Andreassen, Miguel Vidal, Haruhiko Koseki, Artem Barski, Satoshi H Namekawa
During spermatogenesis, a large number of germline genes essential for male fertility are coordinately activated. However, it remains unknown how timely activation of this group of germline genes is accomplished. Here we show that Polycomb-repressive complex 1 (PRC1) directs timely activation of germline genes during spermatogenesis. Inactivation of PRC1 in male germ cells results in the gradual loss of a stem cell population and severe differentiation defects, leading to male infertility. In the stem cell population, RNF2, the dominant catalytic subunit of PRC1, activates transcription of Sall4, which codes for a transcription factor essential for subsequent spermatogenic differentiation...
September 18, 2017: Genes & Development
https://www.readbyqxmd.com/read/28916711/comparative-analysis-of-three-dimensional-chromosomal-architecture-identifies-a-novel-fetal-hemoglobin-regulatory-element
#3
Peng Huang, Cheryl A Keller, Belinda Giardine, Jeremy D Grevet, James O J Davies, Jim R Hughes, Ryo Kurita, Yukio Nakamura, Ross C Hardison, Gerd A Blobel
Chromatin structure is tightly intertwined with transcription regulation. Here we compared the chromosomal architectures of fetal and adult human erythroblasts and found that, globally, chromatin structures and compartments A/B are highly similar at both developmental stages. At a finer scale, we detected distinct folding patterns at the developmentally controlled β-globin locus. Specifically, new fetal stage-specific contacts were uncovered between a region separating the fetal (γ) and adult (δ and β) globin genes (encompassing the HBBP1 and BGLT3 noncoding genes) and two distal chromosomal sites (HS5 and 3'HS1) that flank the locus...
September 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28916710/apc-sets-the-wnt-tone-necessary-for-cerebral-cortical-progenitor-development
#4
Naoki Nakagawa, Jingjun Li, Keiko Yabuno-Nakagawa, Tae-Yeon Eom, Martis Cowles, Tavien Mapp, Robin Taylor, E S Anton
Adenomatous polyposis coli (APC) regulates the activity of β-catenin, an integral component of Wnt signaling. However, the selective role of the APC-β-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated β-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-β-catenin pathway indicates that the maintenance of appropriate β-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex...
September 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28903980/uniform-gene-expression-in-embryos-is-achieved-by-temporal-averaging-of-transcription-noise
#5
L Carine Stapel, Christoph Zechner, Nadine L Vastenhouw
Transcription is often stochastic. This is seemingly incompatible with the importance of gene expression during development. Here we show that during zebrafish embryogenesis, transcription activation is stochastic due to (1) genes acquiring transcriptional competence at different times in different cells, (2) differences in cell cycle stage between cells, and (3) the stochastic nature of transcription. Initially, stochastic transcription causes large cell-to-cell differences in transcript levels. However, variability is reduced by lengthening cell cycles and the accumulation of transcription events in each cell...
September 13, 2017: Genes & Development
https://www.readbyqxmd.com/read/28903979/calcium-dependent-o-glcnac-signaling-drives-liver-autophagy-in-adaptation-to-starvation
#6
Hai-Bin Ruan, Yina Ma, Sara Torres, Bichen Zhang, Colleen Feriod, Ryan M Heck, Kevin Qian, Minnie Fu, Xiuqi Li, Michael H Nathanson, Anton M Bennett, Yongzhan Nie, Barbara E Ehrlich, Xiaoyong Yang
Starvation induces liver autophagy, which is thought to provide nutrients for use by other organs and thereby maintain whole-body homeostasis. Here we demonstrate that O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is required for glucagon-stimulated liver autophagy and metabolic adaptation to starvation. Genetic ablation of OGT in mouse livers reduces autophagic flux and the production of glucose and ketone bodies. Upon glucagon-induced calcium signaling, calcium/calmodulin-dependent kinase II (CaMKII) phosphorylates OGT, which in turn promotes O-GlcNAc modification and activation of Ulk proteins by potentiating AMPK-dependent phosphorylation...
September 13, 2017: Genes & Development
https://www.readbyqxmd.com/read/28887414/progressive-polarity-loss-and-luminal-collapse-disrupt-tissue-organization-in-carcinoma
#7
Ruba Halaoui, Carlis Rejon, Sudipa June Chatterjee, Joseph Szymborski, Sarkis Meterissian, William J Muller, Atilla Omeroglu, Luke McCaffrey
Epithelial cancers (carcinoma) account for 80%-90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture...
September 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28887413/dynamic-assembly-and-activation-of-estrogen-receptor-%C3%AE-enhancers-through-coregulator-switching
#8
Shino Murakami, Anusha Nagari, W Lee Kraus
Although many features of active transcriptional enhancers have been defined by genomic assays, we lack a clear understanding of the order of events leading to enhancer formation and activation as well as the dynamics of coregulator interactions within the enhancer complex. Here, we used selective loss- or gain-of-function mutants of estrogen receptor α (ERα) to define two distinct phases of ligand-dependent enhancer formation. In the first phase (0-20 min), p300 is recruited to ERα by Mediator as well as p300's acetylhistone-binding bromodomain to promote initial enhancer formation, which is not competent for sustained activation...
September 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28887412/enzymatic-modules-of-the-saga-chromatin-modifying-complex-play-distinct-roles-in-drosophila-gene-expression-and-development
#9
Xuanying Li, Christopher W Seidel, Leanne T Szerszen, Jeffrey J Lange, Jerry L Workman, Susan M Abmayr
The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex is a transcriptional coactivator that contains four different modules of subunits. The intact SAGA complex has been well characterized for its function in transcription regulation and development. However, little is known about the roles of individual modules within SAGA and whether they have any SAGA-independent functions. Here we demonstrate that the two enzymatic modules of Drosophila SAGA are differently required in oogenesis. Loss of the histone acetyltransferase (HAT) activity blocks oogenesis, while loss of the H2B deubiquitinase (DUB) activity does not...
September 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28882854/mutation-of-arabidopsis-smc4-identifies-condensin-as-a-corepressor-of-pericentromeric-transposons-and-conditionally-expressed-genes
#10
Jing Wang, Todd Blevins, Ram Podicheti, Jeremy R Haag, Ek Han Tan, Feng Wang, Craig S Pikaard
In eukaryotes, transcriptionally inactive loci are enriched within highly condensed heterochromatin. In plants, as in mammals, the DNA of heterochromatin is densely methylated and wrapped by histones displaying a characteristic subset of post-translational modifications. Growing evidence indicates that these chromatin modifications are not sufficient for silencing. Instead, they are prerequisites for further assembly of higher-order chromatin structures that are refractory to transcription but not fully understood...
September 7, 2017: Genes & Development
https://www.readbyqxmd.com/read/28882853/neuronal-inhibition-of-the-autophagy-nucleation-complex-extends-life-span-in-post-reproductive-c-elegans
#11
Thomas Wilhelm, Jonathan Byrne, Rebeca Medina, Ena Kolundžić, Johannes Geisinger, Martina Hajduskova, Baris Tursun, Holger Richly
Autophagy is a ubiquitous catabolic process that causes cellular bulk degradation of cytoplasmic components and is generally associated with positive effects on health and longevity. Inactivation of autophagy has been linked with detrimental effects on cells and organisms. The antagonistic pleiotropy theory postulates that some fitness-promoting genes during youth are harmful during aging. On this basis, we examined genes mediating post-reproductive longevity using an RNAi screen. From this screen, we identified 30 novel regulators of post-reproductive longevity, including pha-4 Through downstream analysis of pha-4, we identified that the inactivation of genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1, strongly extend both life span and health span...
September 7, 2017: Genes & Development
https://www.readbyqxmd.com/read/28877934/identification-of-senescent-cell-surface-targetable-protein-dpp4
#12
Kyoung Mi Kim, Ji Heon Noh, Monica Bodogai, Jennifer L Martindale, Xiaoling Yang, Fred E Indig, Sandip K Basu, Kei Ohnuma, Chikao Morimoto, Peter F Johnson, Arya Biragyn, Kotb Abdelmohsen, Myriam Gorospe
Senescent cell accumulation in aging tissues is linked to age-associated diseases and declining function, prompting efforts to eliminate them. Mass spectrometry analysis revealed that DPP4 (dipeptidyl peptidase 4) was selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts. Importantly, the differential presence of DPP4 allowed flow cytometry-mediated isolation of senescent cells using anti-DPP4 antibodies. Moreover, antibody-dependent cell-mediated cytotoxicity (ADCC) assays revealed that the cell surface DPP4 preferentially sensitized senescent, but not dividing, fibroblasts to cytotoxicity by natural killer cells...
September 6, 2017: Genes & Development
https://www.readbyqxmd.com/read/28864445/dissection-of-the-molecular-circuitry-controlling-virulence-in-francisella-tularensis
#13
Bonnie J Cuthbert, Wilma Ross, Amy E Rohlfing, Simon L Dove, Richard L Gourse, Richard G Brennan, Maria A Schumacher
Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from genes encoded on the Francisella pathogenicity island (FPI). An unusual set of Francisella regulators-the heteromeric macrophage growth locus protein A (MglA)-stringent starvation protein A (SspA) complex and the DNA-binding protein pathogenicity island gene regulator (PigR)-activates FPI transcription and thus is essential for virulence...
September 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28838946/histone-locus-regulation-by-the-drosophila-dosage-compensation-adaptor-protein-clamp
#14
Leila E Rieder, Kaitlin P Koreski, Kara A Boltz, Guray Kuzu, Jennifer A Urban, Sarah K Bowman, Anna Zeidman, William T Jordan, Michael Y Tolstorukov, William F Marzluff, Robert J Duronio, Erica N Larschan
The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3-histone4 promoter direct HLB formation in Drosophila In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation...
August 24, 2017: Genes & Development
https://www.readbyqxmd.com/read/28827401/inactivation-of-capicua-in-adult-mice-causes-t-cell-lymphoblastic-lymphoma
#15
Lucía Simón-Carrasco, Osvaldo Graña, Marina Salmón, Harrys K C Jacob, Alejandro Gutierrez, Gerardo Jiménez, Matthias Drosten, Mariano Barbacid
CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects...
August 21, 2017: Genes & Development
https://www.readbyqxmd.com/read/28794186/hfq-links-translation-repression-to-stress-induced-mutagenesis-in-e-coli
#16
Jiandong Chen, Susan Gottesman
Mismatch repair (MMR) is a conserved mechanism exploited by cells to correct DNA replication errors both in growing cells and under nongrowing conditions. Hfq (host factor for RNA bacteriophage Qβ replication), a bacterial Lsm family RNA-binding protein, chaperones RNA-RNA interactions between regulatory small RNAs (sRNAs) and target messenger RNAs (mRNAs), leading to alterations of mRNA translation and/or stability. Hfq has been reported to post-transcriptionally repress the DNA MMR gene mutS in stationary phase, possibly limiting MMR to allow increased mutagenesis...
August 9, 2017: Genes & Development
https://www.readbyqxmd.com/read/28794185/id-genes-are-essential-for-early-heart-formation
#17
Thomas J Cunningham, Michael S Yu, Wesley L McKeithan, Sean Spiering, Florent Carrette, Chun-Teng Huang, Paul J Bushway, Matthew Tierney, Sonia Albini, Mauro Giacca, Miguel Mano, Pier Lorenzo Puri, Alessandra Sacco, Pilar Ruiz-Lozano, Jean-Francois Riou, Muriel Umbhauer, Gregg Duester, Mark Mercola, Alexandre R Colas
Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation is initiated during embryonic development and for applying stem cell biology to regenerative medicine and disease modeling. Using systematic and unbiased functional screening approaches, we discovered that the Id family of helix-loop-helix proteins is both necessary and sufficient to direct cardiac mesoderm formation in frog embryos and human embryonic stem cells. Mechanistically, Id proteins specify cardiac cell fate by repressing two inhibitors of cardiogenic mesoderm formation-Tcf3 and Foxa2-and activating inducers Evx1, Grrp1, and Mesp1...
August 9, 2017: Genes & Development
https://www.readbyqxmd.com/read/28794184/post-transcriptional-regulation-of-mouse-neurogenesis-by-pumilio-proteins
#18
Meng Zhang, Dong Chen, Jing Xia, Wenqi Han, Xiekui Cui, Nils Neuenkirchen, Gretchen Hermes, Nenad Sestan, Haifan Lin
Despite extensive studies on mammalian neurogenesis, its post-transcriptional regulation remains under-explored. Here we report that neural-specific inactivation of two murine post-transcriptional regulators, Pumilio 1 (Pum1) and Pum2, severely reduced the number of neural stem cells (NSCs) in the postnatal dentate gyrus (DG), drastically increased perinatal apoptosis, altered DG cell composition, and impaired learning and memory. Consistently, the mutant DG neurospheres generated fewer NSCs with defects in proliferation, survival, and differentiation, supporting a major role of Pum1 and Pum2 in hippocampal neurogenesis and function...
August 9, 2017: Genes & Development
https://www.readbyqxmd.com/read/28790158/lung-tumors-with-distinct-p53-mutations-respond-similarly-to-p53-targeted-therapy-but-exhibit-genotype-specific-statin-sensitivity
#19
Frances K Turrell, Emma M Kerr, Meiling Gao, Hannah Thorpe, Gary J Doherty, Jake Cridge, David Shorthouse, Alyson Speed, Shamith Samarajiwa, Benjamin A Hall, Meryl Griffiths, Carla P Martins
Lung adenocarcinoma accounts for ∼40% of lung cancers, the leading cause of cancer-related death worldwide, and current therapies provide only limited survival benefit. Approximately half of lung adenocarcinomas harbor mutations in TP53 (p53), making these mutants appealing targets for lung cancer therapy. As mutant p53 remains untargetable, mutant p53-dependent phenotypes represent alternative targeting opportunities, but the prevalence and therapeutic relevance of such effects (gain of function and dominant-negative activity) in lung adenocarcinoma are unclear...
August 8, 2017: Genes & Development
https://www.readbyqxmd.com/read/28790157/sirt7-and-the-dead-box-helicase-ddx21-cooperate-to-resolve-genomic-r-loops-and-safeguard-genome-stability
#20
Chenlin Song, Agnes Hotz-Wagenblatt, Renate Voit, Ingrid Grummt
R loops are three-stranded nucleic acid structures consisting of an RNA:DNA heteroduplex and a "looped-out" nontemplate strand. As aberrant formation and persistence of R loops block transcription elongation and cause DNA damage, mechanisms that resolve R loops are essential for genome stability. Here we show that the DEAD (Asp-Glu-Ala-Asp)-box RNA helicase DDX21 efficiently unwinds R loops and that depletion of DDX21 leads to accumulation of cellular R loops and DNA damage. Significantly, the activity of DDX21 is regulated by acetylation...
August 8, 2017: Genes & Development
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