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  • ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-17
    Huijuan Fan,Xuxiang Wang,Wenyang Li,Minhong Shen,Yong Wei,Hanqiu Zheng,Yibin Kang

    Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets

    更新日期:2020-09-17
  • Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-17
    Wenyang Li,Minhong Shen,Yi-Zhou Jiang,Ruina Zhang,Hanqiu Zheng,Yong Wei,Zhi-Ming Shao,Yibin Kang

    SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation

    更新日期:2020-09-17
  • The DNA replication fork suppresses CMG unloading from chromatin before termination.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-17
    Emily Low,Gheorghe Chistol,Manal S Zaher,Olga V Kochenova,Johannes C Walter

    When converging replication forks meet during replication termination, the CMG (Cdc45–MCM2–7–GINS) helicase is polyubiquitylated by CRL2Lrr1 and unloaded from chromatin by the p97 ATPase. Here, we investigate the signal that triggers CMG unloading in Xenopus egg extracts using single-molecule and ensemble approaches. We show that converging CMGs pass each other and keep translocating at the same speed

    更新日期:2020-09-17
  • Context-dependent functional compensation between Ythdf m6A reader proteins.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-17
    Lior Lasman,Vladislav Krupalnik,Sergey Viukov,Nofar Mor,Alejandro Aguilera-Castrejon,Dan Schneir,Jonathan Bayerl,Orel Mizrahi,Shani Peles,Shadi Tawil,Shashank Sathe,Aharon Nachshon,Tom Shani,Mirie Zerbib,Itay Kilimnik,Stefan Aigner,Archana Shankar,Jasmine R Mueller,Schraga Schwartz,Noam Stern-Ginossar,Gene W Yeo,Shay Geula,Noa Novershtern,Jacob H Hanna

    The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins, consists of three homologous m6A-binding proteins, Ythdf1

    更新日期:2020-09-17
  • Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-10
    Bryan King,Jingwen Araki,Wilhelm Palm,Craig B Thompson

    The uptake of macromolecules and cellular debris through macropinocytosis has emerged as an important nutrient acquisition strategy of cancer cells. Genetic alterations commonly found in human cancers (e.g. mutations in KRAS or loss of PTEN) have been shown to increase macropinocytosis. To identify additional effectors that enable cell growth dependent on the uptake of extracellular proteins, pancreatic

    更新日期:2020-09-10
  • AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-10
    Jeanine L Van Nostrand,Kristina Hellberg,En-Ching Luo,Eric L Van Nostrand,Alina Dayn,Jingting Yu,Maxim N Shokhirev,Yelena Dayn,Gene W Yeo,Reuben J Shaw

    Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB, but several lines of evidence

    更新日期:2020-09-10
  • SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-10
    Alison D Parisian,Tomoyuki Koga,Shunichiro Miki,Pascal D Johann,Marcel Kool,John R Crawford,Frank B Furnari

    Atypical teratoid rhabdoid tumors (ATRTs) are challenging pediatric brain cancers that are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes. To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1

    更新日期:2020-09-10
  • Point-activated ESR1Y541S has a dramatic effect on the development of sexually dimorphic organs.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-10
    Alexandra M Simond,Chen Ling,Michaela J Moore,Stephanie A Condotta,Martin J Richer,William J Muller

    Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals

    更新日期:2020-09-10
  • Break-induced replication promotes fragile telomere formation.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-03
    Zhe Yang,Kaori K Takai,Courtney A Lovejoy,Titia de Lange

    TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres—structures that resemble common fragile sites (CFSs)—but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand

    更新日期:2020-09-03
  • Distinct kinesin motors drive two types of maize neocentromeres.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Kyle W Swentowsky,Jonathan I Gent,Elizabeth G Lowry,Veit Schubert,Xia Ran,Kuo-Fu Tseng,Alex E Harkess,Weihong Qiu,R Kelly Dawe

    A maize chromosome variant called abnormal chromosome 10 (Ab10) converts knobs on chromosome arms into neocentromeres, causing their preferential segregation to egg cells in a process known as meiotic drive. We previously demonstrated that the gene Kinesin driver (Kindr) on Ab10 encodes a kinesin-14 required to mobilize neocentromeres made up of the major tandem repeat knob180. Here we describe a second

    更新日期:2020-09-01
  • MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Eli Grunblatt,Nan Wu,Huajia Zhang,Xiaoli Liu,Justin P Norton,Yamini Ohol,Paul Leger,Joseph B Hiatt,Emily C Eastwood,Rhiana Thomas,Ali H Ibrahim,Deshui Jia,Ryan Basom,Keith D Eaton,Renato Martins,A McGarry Houghton,David MacPherson

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed

    更新日期:2020-09-01
  • In vivo CRISPR screening for phenotypic targets of the mir-35-42 family in C. elegans.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Bing Yang,Matthew Schwartz,Katherine McJunkin

    Identifying miRNA target genes is difficult, and delineating which targets are the most biologically important is even more difficult. We devised a novel strategy to test the phenotypic impact of individual microRNA–target interactions by disrupting each predicted miRNA-binding site by CRISPR–Cas9 genome editing in C. elegans. We developed a multiplexed negative selection screening approach in which

    更新日期:2020-09-01
  • Phf21b imprints the spatiotemporal epigenetic switch essential for neural stem cell differentiation.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Amitava Basu,Iván Mestres,Sanjeeb Kumar Sahu,Neha Tiwari,Bimola Khongwir,Jan Baumgart,Aditi Singh,Federico Calegari,Vijay K Tiwari

    Cerebral cortical development in mammals involves a highly complex and organized set of events including the transition of neural stem and progenitor cells (NSCs) from proliferative to differentiative divisions to generate neurons. Despite progress, the spatiotemporal regulation of this proliferation-differentiation switch during neurogenesis and the upstream epigenetic triggers remain poorly known

    更新日期:2020-09-01
  • The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Xiaoyun Ding,Juyeon Jo,Chih-Yen Wang,Carlo D Cristobal,Zhongyuan Zuo,Qi Ye,Marvin Wirianto,Aaron Lindeke-Myers,Jong Min Choi,Carrie A Mohila,Hiroshi Kawabe,Sung Yun Jung,Hugo J Bellen,Seung-Hee Yoo,Hyun Kyoung Lee

    Dysregulation of the ubiquitin–proteasomal system (UPS) enables pathogenic accumulation of disease-driving proteins in neurons across a host of neurological disorders. However, whether and how the UPS contributes to oligodendrocyte dysfunction and repair after white matter injury (WMI) remains undefined. Here we show that the E3 ligase VHL interacts with Daam2 and their mutual antagonism regulates

    更新日期:2020-09-01
  • Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Lena M Kutscher,Konstantin Okonechnikov,Nadja V Batora,Jessica Clark,Patricia B G Silva,Mikaella Vouri,Sjoerd van Rijn,Laura Sieber,Britta Statz,Micah D Gearhart,Ryo Shiraishi,Norman Mack,Brent A Orr,Andrey Korshunov,Brian L Gudenas,Kyle S Smith,Audrey L Mercier,Olivier Ayrault,Mikio Hoshino,Marcel Kool,Katja von Hoff,Norbert Graf,Gudrun Fleischhack,Vivian J Bardwell,Stefan M Pfister,Paul A Northcott

    Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer

    更新日期:2020-09-01
  • miR760 regulates ATXN1 levels via interaction with its 5' untranslated region.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Larissa Nitschke,Ambika Tewari,Stephanie L Coffin,Eder Xhako,Kaifang Pang,Vincenzo A Gennarino,Jennifer L Johnson,Francisco A Blanco,Zhandong Liu,Huda Y Zoghbi

    Identifying modifiers of dosage-sensitive genes involved in neurodegenerative disorders is imperative to discover novel genetic risk factors and potential therapeutic entry points. In this study, we focus on Ataxin-1 (ATXN1), a dosage-sensitive gene involved in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1). While the precise maintenance of ATXN1 levels is essential to prevent disease

    更新日期:2020-09-01
  • p53 tetramerization: at the center of the dominant-negative effect of mutant p53.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Jovanka Gencel-Augusto,Guillermina Lozano

    The p53 tumor suppressor functions as a tetrameric transcription factor to regulate hundreds of genes—many in a tissue-specific manner. Missense mutations in cancers in the p53 DNA-binding and tetramerization domains cement the importance of these domains in tumor suppression. p53 mutants with a functional tetramerization domain form mixed tetramers, which in some cases have dominant-negative effects

    更新日期:2020-09-01
  • The nuclear cap-binding complex as choreographer of gene transcription and pre-mRNA processing.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Xavier Rambout,Lynne E Maquat

    The largely nuclear cap-binding complex (CBC) binds to the 5′ caps of RNA polymerase II (RNAPII)-synthesized transcripts and serves as a dynamic interaction platform for a myriad of RNA processing factors that regulate gene expression. While influence of the CBC can extend into the cytoplasm, here we review the roles of the CBC in the nucleus, with a focus on protein-coding genes. We discuss differences

    更新日期:2020-09-01
  • Mixed knobs in corn cobs.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Piero Lamelza,Michael A Lampson

    Maize heterochromatic knobs cheat female meiosis by forming neocentromeres that bias their segregation into the future egg cell. In this issue of Genes & Development, Swentowsky and colleagues (pp. 1239–1251) show that two types of knobs, those composed of 180-bp and TR1 sequences, recruit their own novel and divergent kinesin-14 family members to form neocentromeres.

    更新日期:2020-09-01
  • UTteR control through miRs: fine-tuning ATXN1 levels to prevent ataxia.
    Genes Dev. (IF 9.527) Pub Date : 2020-09-01
    Mingyi Xie,Maurice S Swanson

    Pathomechanistic studies of neurodegenerative diseases have documented the toxic effects of mutant protein expression, misfolding, and aggregation. However, alterations in the expression of the corresponding wild-type (WT) gene, due to either variations in copy number or transcriptional regulation, have also been linked to Alzheimer's and Parkinson's diseases. Another striking example of this mutant

    更新日期:2020-09-01
  • Erratum: Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    R A Greenstein,Ramon R Barrales,Nicholas A Sanchez,Jordan E Bisanz,Sigurd Braun,Bassem Al-Sady

    Genes & Development 34: 99–117 (2020)

    更新日期:2020-08-03
  • A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Biliana Marcheva,Mark Perelis,Benjamin J Weidemann,Akihiko Taguchi,Haopeng Lin,Chiaki Omura,Yumiko Kobayashi,Marsha V Newman,Eugene J Wyatt,Elizabeth M McNally,Jocelyn E Manning Fox,Heekyung Hong,Archana Shankar,Emily C Wheeler,Kathryn Moynihan Ramsey,Patrick E MacDonald,Gene W Yeo,Joseph Bass

    The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic β cells that are perturbed in Clock−/− and Bmal1−/− β-cell lines. We show that the

    更新日期:2020-08-03
  • Identification of a localized nonsense-mediated decay pathway at the endoplasmic reticulum.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Dasa Longman,Kathryn A Jackson-Jones,Magdalena M Maslon,Laura C Murphy,Robert S Young,Jack J Stoddart,Nele Hug,Martin S Taylor,Dimitrios K Papadopoulos,Javier F Cáceres

    Nonsense-mediated decay (NMD) is a translation-dependent RNA quality control mechanism that occurs in the cytoplasm. However, it is unknown how NMD regulates the stability of RNAs translated at the endoplasmic reticulum (ER). Here, we identify a localized NMD pathway dedicated to ER-translated mRNAs. We previously identified NBAS, a component of the Syntaxin 18 complex involved in Golgi-to-ER trafficking

    更新日期:2020-08-03
  • Human RTEL1 associates with Poldip3 to facilitate responses to replication stress and R-loop resolution.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Andrea Björkman,Søren L Johansen,Lin Lin,Mike Schertzer,Dimitris C Kanellis,Anna-Maria Katsori,Søren T Christensen,Yonglun Luo,Jens S Andersen,Simon J Elsässer,Arturo Londono-Vallejo,Jiri Bartek,Kenneth B Schou

    RTEL1 helicase is a component of DNA repair and telomere maintenance machineries. While RTEL1's role in DNA replication is emerging, how RTEL1 preserves genomic stability during replication remains elusive. Here we used a range of proteomic, biochemical, cell, and molecular biology and gene editing approaches to provide further insights into potential role(s) of RTEL1 in DNA replication and genome

    更新日期:2020-08-03
  • Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Frank Szulzewsky,Sonali Arora,Pia Hoellerbauer,Claire King,Erica Nathan,Marina Chan,Patrick J Cimino,Tatsuya Ozawa,Daisuke Kawauchi,Kristian W Pajtler,Richard J Gilbertson,Patrick J Paddison,Valeri Vasioukhin,Taranjit S Gujral,Eric C Holland

    YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3,

    更新日期:2020-08-03
  • Neural production of kynurenic acid in Caenorhabditis elegans requires the AAT-1 transporter.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Lin Lin,George A Lemieux,Osatohanmwen Jessica Enogieru,Kathleen M Giacomini,Kaveh Ashrafi

    Kynurenic acid (KynA) levels link peripheral metabolic status to neural functions including learning and memory. Since neural KynA levels dampen learning capacity, KynA reduction has been proposed as a therapeutic strategy for conditions of cognitive deficit such as neurodegeneration. While KynA is generated locally within the nervous system, its precursor, kynurenine (Kyn), is largely derived from

    更新日期:2020-08-03
  • Collapse of the hepatic gene regulatory network in the absence of FoxA factors.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Yitzhak Reizel,Ashleigh Morgan,Long Gao,Yemin Lan,Elisabetta Manduchi,Eric L Waite,Amber W Wang,Andrew Wells,Klaus H Kaestner

    The FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex regulatory network thought to become progressively resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for maintaining this regulatory network, we ablated all FoxA genes in the

    更新日期:2020-08-03
  • Cells of origin of lung cancers: lessons from mouse studies.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Giustina Ferone,Myung Chang Lee,Julien Sage,Anton Berns

    As one of the most common forms of cancer, lung cancers present as a collection of different histological subtypes. These subtypes are characterized by distinct sets of driver mutations and phenotypic appearance, and they often show varying degrees of heterogenicity, aggressiveness, and response/resistance to therapy. Intriguingly, lung cancers are also capable of showing features of multiple subtypes

    更新日期:2020-08-03
  • Alternative splicing and cancer: insights, opportunities, and challenges from an expanding view of the transcriptome.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    Sara Cherry,Kristen W Lynch

    Over the past decade there has been increased awareness of the potential role of alternative splicing in the etiology of cancer. In particular, advances in RNA-Sequencing technology and analysis has led to a wave of discoveries in the last few years regarding the causes and functional relevance of alternative splicing in cancer. Here we discuss the current understanding of the connections between splicing

    更新日期:2020-08-03
  • FoxA factors: the chromatin key and doorstop essential for liver development and function.
    Genes Dev. (IF 9.527) Pub Date : 2020-08-01
    James A Heslop,Stephen A Duncan

    Pioneer factors are transcriptional regulators with the capacity to bind inactive regions of chromatin and induce changes in accessibility that underpin cell fate decisions. The FOXA family of transcription factors is well understood to have pioneer capacity. Indeed, researchers have uncovered numerous examples of FOXA-dependent epigenomic modulation in developmental and disease processes. Despite

    更新日期:2020-08-03
  • Competition between maturation and degradation drives human snRNA 3' end quality control.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Rea M Lardelli,Jens Lykke-Andersen

    Polymerases and exonucleases act on 3′ ends of nascent RNAs to promote their maturation or degradation but how the balance between these activities is controlled to dictate the fates of cellular RNAs remains poorly understood. Here, we identify a central role for the human DEDD deadenylase TOE1 in distinguishing the fates of small nuclear (sn)RNAs of the spliceosome from unstable genome-encoded snRNA

    更新日期:2020-07-01
  • HDAC3 ensures stepwise epidermal stratification via NCoR/SMRT-reliant mechanisms independent of its histone deacetylase activity.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Katherine M Szigety,Fang Liu,Chase Y Yuan,Deborah J Moran,Jeremy Horrell,Heather R Gochnauer,Ronald N Cohen,Jonathan P Katz,Klaus H Kaestner,John T Seykora,John W Tobias,Mitchell A Lazar,Mingang Xu,Sarah E Millar

    Chromatin modifiers play critical roles in epidermal development, but the functions of histone deacetylases in this context are poorly understood. The class I HDAC, HDAC3, is of particular interest because it plays divergent roles in different tissues by partnering with tissue-specific transcription factors. We found that HDAC3 is expressed broadly in embryonic epidermis and is required for its orderly

    更新日期:2020-07-01
  • Twist-dependent ratchet functioning downstream from Dorsal revealed using a light-inducible degron.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Jihyun Irizarry,James McGehee,Goheun Kim,David Stein,Angelike Stathopoulos

    Graded transcription factors are pivotal regulators of embryonic patterning, but whether their role changes over time is unclear. A light-regulated protein degradation system was used to assay temporal dependence of the transcription factor Dorsal in dorsal–ventral axis patterning of Drosophila embryos. Surprisingly, the high-threshold target gene snail only requires Dorsal input early but not late

    更新日期:2020-07-01
  • Transcriptional regulatory network controlling the ontogeny of hematopoietic stem cells.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Peng Gao,Changya Chen,Elizabeth D Howell,Yan Li,Joanna Tober,Yasin Uzun,Bing He,Long Gao,Qin Zhu,Arndt F Siekmann,Nancy A Speck,Kai Tan

    Hematopoietic stem cell (HSC) ontogeny is accompanied by dynamic changes in gene regulatory networks. We performed RNA-seq and histone mark ChIP-seq to define the transcriptomes and epigenomes of cells representing key developmental stages of HSC ontogeny in mice. The five populations analyzed were embryonic day 10.5 (E10.5) endothelium and hemogenic endothelium from the major arteries, an enriched

    更新日期:2020-07-01
  • A central role for canonical PRC1 in shaping the 3D nuclear landscape.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Shelagh Boyle,Ilya M Flyamer,Iain Williamson,Dipta Sengupta,Wendy A Bickmore,Robert S Illingworth

    Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role

    更新日期:2020-07-01
  • Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Hyeseon Kang,Maxim N Shokhirev,Zhichao Xu,Sahaana Chandran,Jesse R Dixon,Martin W Hetzer

    During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications

    更新日期:2020-07-01
  • UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Carmen Pérez-Calero,Aleix Bayona-Feliu,Xiaoyu Xue,Sonia I Barroso,Sergio Muñoz,Víctor M González-Basallote,Patrick Sung,Andrés Aguilera

    Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B

    更新日期:2020-07-01
  • Nutrient-dependent control of RNA polymerase II elongation rate regulates specific gene expression programs by alternative polyadenylation.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Carlo Yague-Sanz,Yann Vanrobaeys,Ronan Fernandez,Maxime Duval,Marc Larochelle,Jude Beaudoin,Julien Berro,Simon Labbé,Pierre-Étienne Jacques,François Bachand

    Transcription by RNA polymerase II (RNAPII) is a dynamic process with frequent variations in the elongation rate. However, the physiological relevance of variations in RNAPII elongation kinetics has remained unclear. Here we show in yeast that a RNAPII mutant that reduces the transcription elongation rate causes widespread changes in alternative polyadenylation (APA). We unveil two mechanisms by which

    更新日期:2020-07-01
  • RNA polymerase III transcription as a disease factor.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Meghdad Yeganeh,Nouria Hernandez

    RNA polymerase (Pol) III is responsible for transcription of different noncoding genes in eukaryotic cells, whose RNA products have well-defined functions in translation and other biological processes for some, and functions that remain to be defined for others. For all of them, however, new functions are being described. For example, Pol III products have been reported to regulate certain proteins

    更新日期:2020-07-01
  • A genome-wide and cotranscriptional suppressor of R loops.
    Genes Dev. (IF 9.527) Pub Date : 2020-07-01
    Jacob P Matson,Lee Zou

    R loops arise from hybridization of RNA transcripts with template DNA during transcription. Unrepaired R loops lead to transcription–replication collisions, causing DNA damage and genomic instability. In this issue of Genes & Development, Pérez-Calero and colleagues (pp. 898–912) identify UAP56 as a cotranscriptional RNA–DNA helicase that unwinds R loops. They found that UAP56 helicase activity is

    更新日期:2020-07-01
  • Corrigendum: Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Dan Lu,Ho-Su Sin,Chenggang Lu,Margaret T Fuller

    Genes & Development 34: 663–677 (2020)

    更新日期:2020-06-01
  • Progress toward understanding chromosome silencing by Xist RNA.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Neil Brockdorff,Joseph S Bowness,Guifeng Wei

    The X inactive-specific transcript (Xist) gene is the master regulator of X chromosome inactivation in mammals. Xist produces a long noncoding (lnc)RNA that accumulates over the entire length of the chromosome from which it is transcribed, recruiting factors to modify underlying chromatin and silence X-linked genes in cis. Recent years have seen significant progress in identifying important functional

    更新日期:2020-06-01
  • After the break: DSB end processing in mouse meiosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Kevin Brick,Florencia Pratto,R Daniel Camerini-Otero

    The exchange of genetic information between parental chromosomes in meiosis is an integral process for the creation of gametes. To generate a crossover, hundreds of DNA double-strand breaks (DSBs) are introduced in the genome of each meiotic cell by the SPO11 protein. The nucleolytic resection of DSB-adjacent DNA is a key step in meiotic DSB repair, but this process has remained understudied. In this

    更新日期:2020-06-01
  • Transcriptional down-regulation of metabolic genes by Gdown1 ablation induces quiescent cell re-entry into the cell cycle.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Miki Jishage,Keiichi Ito,Chi-Shuen Chu,Xiaoling Wang,Masashi Yamaji,Robert G Roeder

    Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through

    更新日期:2020-06-01
  • ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Yueh-Lin Tsai,Tristan H Coady,Lei Lu,Dinghai Zheng,Isabel Alland,Bin Tian,Neil A Shneider,James L Manley

    Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives

    更新日期:2020-06-01
  • TEX15 associates with MILI and silences transposable elements in male germ cells.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Fang Yang,Yemin Lan,Radha Raman Pandey,David Homolka,Shelley L Berger,Ramesh S Pillai,Marisa S Bartolomei,P Jeremy Wang

    DNA methylation is a major silencing mechanism of transposable elements (TEs). Here we report that TEX15, a testis-specific protein, is required for TE silencing. TEX15 is expressed in embryonic germ cells and functions during genome-wide epigenetic reprogramming. The Tex15 mutant exhibits DNA hypomethylation in TEs at a level similar to Mili and Dnmt3c but not Miwi2 mutants. TEX15 is associated with

    更新日期:2020-06-01
  • 4E-T-bound mRNAs are stored in a silenced and deadenylated form.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Felix Räsch,Ramona Weber,Elisa Izaurralde,Cátia Igreja

    Human 4E-T is an eIF4E-binding protein (4E-BP) present in processing (P)-bodies that represses translation and regulates decay of mRNAs destabilized by AU-rich elements and microRNAs (miRNAs). However, the underlying regulatory mechanisms are still unclear. Here, we show that upon mRNA binding 4E-T represses translation and promotes deadenylation via the recruitment of the CCR4–NOT deadenylase complex

    更新日期:2020-06-01
  • Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Kimberly A Rickman,Raymond J Noonan,Francis P Lach,Sunandini Sridhar,Anderson T Wang,Avinash Abhyankar,Athena Huang,Michael Kelly,Arleen D Auerbach,Agata Smogorzewska

    DNA interstrand cross-links (ICLs) are a form of DNA damage that requires the interplay of a number of repair proteins including those of the Fanconi anemia (FA) and the homologous recombination (HR) pathways. Pathogenic variants in the essential gene BRCA2/FANCD1, when monoallelic, predispose to breast and ovarian cancer, and when biallelic, result in a severe subtype of Fanconi anemia. BRCA2 function

    更新日期:2020-06-01
  • Molecular structures and mechanisms of DNA break processing in mouse meiosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Shintaro Yamada,Anjali Gupta Hinch,Hisashi Kamido,Yongwei Zhang,Winfried Edelmann,Scott Keeney

    Exonucleolytic resection, critical to repair double-strand breaks (DSBs) by recombination, is not well understood, particularly in mammalian meiosis. Here, we define structures of resected DSBs in mouse spermatocytes genome-wide at nucleotide resolution. Resection tracts averaged 1100 nt, but with substantial fine-scale heterogeneity at individual hot spots. Surprisingly, EXO1 is not the major 5′ →

    更新日期:2020-06-01
  • The spatial regulation of condensin activity in chromosome condensation.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Rebecca Lamothe,Lorenzo Costantino,Douglas E Koshland

    Condensin mediates chromosome condensation, which is essential for proper chromosome segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses to a thin loop that is distinct from the rest of the chromosomes. We provide evidence that the establishment and maintenance of this RDN condensation requires the regulation of condensin by Cdc5p (polo) kinase. We show

    更新日期:2020-06-01
  • REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors.
    Genes Dev. (IF 9.527) Pub Date : 2020-06-01
    Shuxi Qiao,Siang-Boon Koh,Varunika Vivekanandan,Devika Salunke,Krushna Chandra Patra,Elma Zaganjor,Kenneth Ross,Yusuke Mizukami,Sarah Jeanfavre,Athena Chen,Mari Mino-Kenudson,Sridhar Ramaswamy,Clary Clish,Marcia Haigis,Nabeel Bardeesy,Leif W Ellisen

    Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion

    更新日期:2020-06-01
  • Getting started: altering promoter choice as a mechanism for cell type differentiation.
    Genes Dev. (IF 9.527) Pub Date : 2020-05-01
    Mukulika Ray,Erica Larschan

    In this issue of Genes & Development, Lu and colleagues (pp. 663-677) have discovered a key new mechanism of alternative promoter choice that is involved in differentiation of spermatocytes. Promoter choice has strong potential as mechanism for differentiation of many different cell types.

    更新日期:2020-05-01
  • Targeted chemotherapy overcomes drug resistance in melanoma.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-02
    Jingyin Yue,Roberto Vendramin,Fan Liu,Omar Lopez,Monica G Valencia,Helena Gomes Dos Santos,Gabriel Gaidosh,Felipe Beckedorff,Ezra Blumenthal,Lucia Speroni,Stephen D Nimer,Jean-Christophe Marine,Ramin Shiekhattar

    The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed "targeted chemotherapy" by depleting protein phosphatase 2A (PP2A) or

    更新日期:2020-05-01
  • Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons.
    Genes Dev. (IF 9.527) Pub Date : 2020-04-02
    Bishakha Mona,Juan Villarreal,Trisha K Savage,Rahul K Kollipara,Brooke E Boisvert,Jane E Johnson

    Peripheral somatosensory input is modulated in the dorsal spinal cord by a network of excitatory and inhibitory interneurons. PTF1A is a transcription factor essential in dorsal neural tube progenitors for specification of these inhibitory neurons. Thus, mechanisms regulating Ptf1a expression are key for generating neuronal circuits underlying somatosensory behaviors. Mutations targeted to distinct

    更新日期:2020-05-01
  • Embryo integrity regulates maternal proteostasis and stress resilience.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Ambre J Sala,Laura C Bott,Renee M Brielmann,Richard I Morimoto

    The proteostasis network is regulated by transcellular communication to promote health and fitness in metazoans. In Caenorhabditis elegans, signals from the germline initiate the decline of proteostasis and repression of cell stress responses at reproductive maturity, indicating that commitment to reproduction is detrimental to somatic health. Here we show that proteostasis and stress resilience are

    更新日期:2020-05-01
  • Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Taylor K Loe,Julia Su Zhou Li,Yuxiang Zhang,Benura Azeroglu,Michael Nicholas Boddy,Eros Lazzerini Denchi

    Telomeres consist of TTAGGG repeats bound by protein complexes that serve to protect the natural end of linear chromosomes. Most cells maintain telomere repeat lengths by using the enzyme telomerase, although there are some cancer cells that use a telomerase-independent mechanism of telomere extension, termed alternative lengthening of telomeres (ALT). Cells that use ALT are characterized, in part

    更新日期:2020-05-01
  • The rRNA m6A methyltransferase METTL5 is involved in pluripotency and developmental programs.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Valentina V Ignatova,Paul Stolz,Steffen Kaiser,Tobias H Gustafsson,Palma Rico Lastres,Adrián Sanz-Moreno,Yi-Li Cho,Oana V Amarie,Antonio Aguilar-Pimentel,Tanja Klein-Rodewald,Julia Calzada-Wack,Lore Becker,Susan Marschall,Markus Kraiger,Lillian Garrett,Claudia Seisenberger,Sabine M Hölter,Kayla Borland,Erik Van De Logt,Pascal W T C Jansen,Marijke P Baltissen,Magdalena Valenta,Michiel Vermeulen,Wolfgang

    Covalent chemical modifications of cellular RNAs directly impact all biological processes. However, our mechanistic understanding of the enzymes catalyzing these modifications, their substrates and biological functions, remains vague. Amongst RNA modifications N6-methyladenosine (m6A) is widespread and found in messenger (mRNA), ribosomal (rRNA), and noncoding RNAs. Here, we undertook a systematic

    更新日期:2020-05-01
  • Developmental regulation of cell type-specific transcription by novel promoter-proximal sequence elements.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-26
    Dan Lu,Ho-Su Sin,Chenggang Lu,Margaret T Fuller

    Cell type-specific transcriptional programs that drive differentiation of specialized cell types are key players in development and tissue regeneration. One of the most dramatic changes in the transcription program in Drosophila occurs with the transition from proliferating spermatogonia to differentiating spermatocytes, with >3000 genes either newly expressed or expressed from new alternative promoters

    更新日期:2020-05-01
  • Autophagy promotes mammalian survival by suppressing oxidative stress and p53.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-19
    Yang Yang,Gizem Karsli-Uzunbas,Laura Poillet-Perez,Akshada Sawant,Zhixian Sherrie Hu,Yuhan Zhao,Dirk Moore,Wenwei Hu,Eileen White

    Autophagy captures intracellular components and delivers them to lysosomes for degradation and recycling. Conditional autophagy deficiency in adult mice causes liver damage, shortens life span to 3 mo due to neurodegeneration, and is lethal upon fasting. As autophagy deficiency causes p53 induction and cell death in neurons, we sought to test whether p53 mediates the lethal consequences of autophagy

    更新日期:2020-05-01
  • Drosophila estrogen-related receptor directs a transcriptional switch that supports adult glycolysis and lipogenesis.
    Genes Dev. (IF 9.527) Pub Date : 2020-03-12
    Katherine Beebe,Marcy M Robins,Edgar J Hernandez,Geanette Lam,Michael A Horner,Carl S Thummel

    Metabolism and development must be closely coupled to meet the changing physiological needs of each stage in the life cycle. The molecular mechanisms that link these pathways, however, remain poorly understood. Here we show that the Drosophila estrogen-related receptor (dERR) directs a transcriptional switch in mid-pupae that promotes glucose oxidation and lipogenesis in young adults. dERR mutant adults

    更新日期:2020-05-01
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