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  • Acute perturbation strategies in interrogating RNA polymerase II elongation factor function in gene expression
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Bin Zheng; Yuki Aoi; Avani P. Shah; Marta Iwanaszko; Siddhartha Das; Emily J. Rendleman; Didi Zha; Nabiha Khan; Edwin R. Smith; Ali Shilatifard

    The regulation of gene expression catalyzed by RNA polymerase II (Pol II) requires a host of accessory factors to ensure cell growth, differentiation, and survival under environmental stress. Here, using the auxin-inducible degradation (AID) system to study transcriptional activities of the bromodomain and extraterminal domain (BET) and super elongation complex (SEC) families, we found that the CDK9-containing

    更新日期:2021-01-14
  • Substrate-dependent effects of quaternary structure on RNase E activity
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Christopher J. Moore; Hayoung Go; Eunkyoung Shin; Hye-Jeong Ha; Saemee Song; Nam-Chul Ha; Yong-Hak Kim; Stanley N. Cohen; Kangseok Lee

    RNase E is an essential, multifunctional ribonuclease encoded in E. coli by the rne gene. Structural analysis indicates that the ribonucleolytic activity of this enzyme is conferred by rne-encoded polypeptide chains that (1) dimerize to form a catalytic site at the protein-protein interface, and (2) multimerize further to generate a tetrameric quaternary structure consisting of two dimerized Rne-peptide

    更新日期:2021-01-14
  • SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic β cells
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Romina J. Bevacqua; Jonathan Y. Lam; Heshan Peiris; Robert L. Whitener; Seokho Kim; Xueying Gu; Mollie S.H. Friedlander; Seung K. Kim

    The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic β cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors

    更新日期:2021-01-14
  • Protein-bound molybdenum cofactor is bioavailable and rescues molybdenum cofactor-deficient C. elegans
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Kurt Warnhoff; Thomas W. Hercher; Ralf R. Mendel; Gary Ruvkun

    The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the

    更新日期:2021-01-14
  • ATDC binds to KEAP1 to drive NRF2-mediated tumorigenesis and chemoresistance in pancreatic cancer
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Vinee Purohit; Lidong Wang; Huibin Yang; Jiufeng Li; Gina M. Ney; Erica R. Gumkowski; Akash J. Vaidya; Annie Wang; Amit Bhardwaj; Ende Zhao; Igor Dolgalev; Andrea Zamperone; Ethan V. Abel; Marina Pasca Di Magliano; Howard C. Crawford; Daniel Diolaiti; Thales Y. Papagiannakopoulos; Costas A. Lyssiotis; Diane M. Simeone

    Pancreatic ductal adenocarcinoma is a lethal disease characterized by late diagnosis, propensity for early metastasis and resistance to chemotherapy. Little is known about the mechanisms that drive innate therapeutic resistance in pancreatic cancer. The ataxia-telangiectasia group D-associated gene (ATDC) is overexpressed in pancreatic cancer and promotes tumor growth and metastasis. Our study reveals

    更新日期:2021-01-14
  • An interplay of NOX1-derived ROS and oxygen determines the spermatogonial stem cell self-renewal efficiency under hypoxia
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Hiroko Morimoto; Takuya Yamamoto; Takehiro Miyazaki; Narumi Ogonuki; Atsuo Ogura; Takashi Tanaka; Mito Kanatsu-Shinohara; Chihiro Yabe-Nishimura; Hongliang Zhang; Yves Pommier; Andreas Trumpp; Takashi Shinohara

    Reactive oxygen species (ROS) produced by NADPH1 oxidase 1 (NOX1) are thought to drive spermatogonial stem cell (SSC) self-renewal through feed-forward production of ROS by the ROS-BCL6B-NOX1 pathway. Here we report the critical role of oxygen on ROS-induced self-renewal. Cultured SSCs proliferated poorly and lacked BCL6B expression under hypoxia despite increase in mitochondria-derived ROS. Due to

    更新日期:2021-01-14
  • Esc2 orchestrates substrate-specific sumoylation by acting as a SUMO E2 cofactor in genome maintenance
    Genes Dev. (IF 9.527) Pub Date : 2021-01-14
    Shibai Li; Jacob N. Bonner; Bingbing Wan; Stephen So; Ashley Summers; Leticia Gonzalez; Xiaoyu Xue; Xiaolan Zhao

    SUMO modification regulates diverse cellular processes by targeting hundreds of proteins. However, the limited number of sumoylation enzymes raises the question of how such a large number of substrates are efficiently modified. Specifically, how genome maintenance factors are dynamically sumoylated at DNA replication and repair sites to modulate their functions is poorly understood. Here, we demonstrate

    更新日期:2021-01-14
  • Corrigendum: Molecular mechanism for the interaction between human CPSF30 and hFip1
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Keith Hamilton; Liang Tong

    Genes & Development 34: 1753–1761 (2020)

    更新日期:2021-01-04
  • Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in flies and mice
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Joseph Salomone; Shenyue Qin; Temesgen D. Fufa; Brittany Cain; Edward Farrow; Bin Guan; Robert B. Hufnagel; Masato Nakafuku; Hee-Woong Lim; Kenneth Campbell; Brian Gebelein

    How homeodomain proteins gain sufficient specificity to control different cell fates has been a long-standing problem in developmental biology. The conserved Gsx homeodomain proteins regulate specific aspects of neural development in animals from flies to mammals, and yet they belong to a large transcription factor family that bind nearly identical DNA sequences in vitro. Here, we show that the mouse

    更新日期:2021-01-04
  • Pioneer-like factor GAF cooperates with PBAP (SWI/SNF) and NURF (ISWI) to regulate transcription
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Julius Judd; Fabiana M. Duarte; John T. Lis

    Transcriptionally silent genes must be activated throughout development. This requires nucleosomes be removed from promoters and enhancers to allow transcription factor (TF) binding and recruitment of coactivators and RNA polymerase II (Pol II). Specialized pioneer TFs bind nucleosome-wrapped DNA to perform this chromatin opening by mechanisms that remain incompletely understood. Here, we show that

    更新日期:2021-01-04
  • A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Myoung Sook Han; Rachel J. Perry; João-Paulo Camporez; Philipp E. Scherer; Gerald I. Shulman; Guangping Gao; Roger J. Davis

    The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine

    更新日期:2021-01-04
  • Differential requirements for MDM2 E3 activity during embryogenesis and in adult mice
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Timothy J. Humpton; Koji Nomura; Julia Weber; Helge M. Magnussen; Andreas K. Hock; Colin Nixon; Sandeep Dhayade; David Stevenson; Danny T. Huang; Douglas Strathdee; Karen Blyth; Karen H. Vousden

    The p53 tumor suppressor protein is a potent activator of proliferative arrest and cell death. In normal cells, this pathway is restrained by p53 protein degradation mediated by the E3-ubiquitin ligase activity of MDM2. Oncogenic stress releases p53 from MDM2 control, so activating the p53 response. However, many tumors that retain wild-type p53 inappropriately maintain the MDM2-p53 regulatory loop

    更新日期:2021-01-04
  • The p53-induced RNA-binding protein ZMAT3 is a splicing regulator that inhibits the splicing of oncogenic CD44 variants in colorectal carcinoma
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Bruna R. Muys; Dimitrios G. Anastasakis; Duncan Claypool; Lörinc Pongor; Xiao Ling Li; Ioannis Grammatikakis; Minxue Liu; Xiantao Wang; Kannanganattu V. Prasanth; Mirit I. Aladjem; Ashish Lal; Markus Hafner

    p53 is an intensely studied tumor-suppressive transcription factor. Recent studies suggest that the RNA-binding protein (RBP) ZMAT3 is important in mediating the tumor-suppressive effects of p53. Here, we globally identify ZMAT3-regulated RNAs and their binding sites at nucleotide resolution in intact colorectal cancer (CRC) cells. ZMAT3 binds to thousands of mRNA precursors, mainly at intronic uridine-rich

    更新日期:2021-01-04
  • Argonaute NRDE-3 and MBT domain protein LIN-61 redundantly recruit an H3K9me3 HMT to prevent embryonic lethality and transposon expression
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Jan Padeken; Stephen Methot; Peter Zeller; Colin E. Delaney; Veronique Kalck; Susan M. Gasser

    The establishment and maintenance of chromatin domains shape the epigenetic memory of a cell, with the methylation of histone H3 lysine 9 (H3K9me) defining transcriptionally silent heterochromatin. We show here that the C. elegans SET-25 (SUV39/G9a) histone methyltransferase (HMT), which catalyzes H3K9me1, me2 and me3, can establish repressed chromatin domains de novo, unlike the SETDB1 homolog MET-2

    更新日期:2021-01-04
  • Calcium signaling instructs NIPBL recruitment at active enhancers and promoters via distinct mechanisms to reconstruct genome compartmentalization
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Yina Zhu; Matthew Denholtz; Hanbin Lu; Cornelis Murre

    During developmental progression the genomes of immune cells undergo large-scale changes in chromatin folding. However, insights into signaling pathways and epigenetic control of nuclear architecture remain rudimentary. Here, we found that in activated neutrophils calcium influx rapidly recruited the cohesin-loading factor NIPBL to thousands of active enhancers and promoters to dictate widespread changes

    更新日期:2021-01-04
  • mTOR inhibition acts as an unexpected checkpoint in p53-mediated tumor suppression
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Ning Kon; Yang Ou; Shang-Jui Wang; Huan Li; Anil K. Rustgi; Wei Gu

    Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover

    更新日期:2021-01-04
  • The missing linker: emerging trends for H1 variant-specific functions
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Laura Prendergast; Danny Reinberg

    Major advances in the chromatin and epigenetics fields have uncovered the importance of core histones, histone variants and their post-translational modifications (PTMs) in modulating chromatin structure. However, an acutely understudied related feature of chromatin structure is the role of linker histone H1. Previous assumptions of the functional redundancy of the 11 nonallelic H1 variants are contrasted

    更新日期:2021-01-04
  • TFs for TEs: the transcription factor repertoire of mammalian transposable elements
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Clara Hermant; Maria-Elena Torres-Padilla

    Transposable elements (TEs) are genetic elements capable of changing position within the genome. Although their mobilization can constitute a threat to genome integrity, nearly half of modern mammalian genomes are composed of remnants of TE insertions. The first critical step for a successful transposition cycle is the generation of a full-length transcript. TEs have evolved cis-regulatory elements

    更新日期:2021-01-04
  • The end protection problem—an unexpected twist in the tail
    Genes Dev. (IF 9.527) Pub Date : 2021-01-01
    Phil Ruis; Simon J. Boulton

    In this perspective, we introduce shelterin and the mechanisms of ATM activation and NHEJ at telomeres, before discussing the following questions: How are t-loops proposed to protect chromosome ends and what is the evidence for this model? Can other models explain how TRF2 mediates end protection? Could t-loops be pathological structures? How is end protection achieved in pluripotent cells? What do

    更新日期:2021-01-04
  • Reviewers, Volume 34 (2020)
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01

    The editors would like to thank the Editorial Board and the following scientists who reviewed papers and provided advice during 2020.

    更新日期:2020-12-01
  • FGF signaling regulates development by processes beyond canonical pathways
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Ayan T. Ray; Pierre Mazot; J. Richard Brewer; Catarina Catela; Colin J. Dinsmore; Philippe Soriano

    FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that

    更新日期:2020-12-01
  • Molecular mechanism for the interaction between human CPSF30 and hFip1
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Keith Hamilton; Liang Tong

    Most eukaryotic pre-mRNAs must undergo 3′-end cleavage and polyadenylation prior to their export from the nucleus. A large number of proteins in several complexes participate in this 3′-end processing, including cleavage and polyadenylation specificity factor (CPSF) in mammals. The CPSF30 subunit contains five CCCH zinc fingers (ZFs), with ZF2–ZF3 being required for the recognition of the AAUAAA poly(A)

    更新日期:2020-12-01
  • DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Joon H. Choi; James M. Burke; Kayla H. Szymanik; Upasana Nepal; Anna Battenhouse; Justin T. Lau; Aaron Stark; Victor Lam; Christopher S. Sullivan

    Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5′-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host

    更新日期:2020-12-01
  • BMP signaling: at the gate between activated melanocyte stem cells and differentiation
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Nicole R. Infarinato; Katherine S. Stewart; Yihao Yang; Nicholas C. Gomez; H. Amalia Pasolli; Lynette Hidalgo; Lisa Polak; Thomas S. Carroll; Elaine Fuchs

    Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics

    更新日期:2020-12-01
  • A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Narendra Pratap Singh; Bony De Kumar; Ariel Paulson; Mark E. Parrish; Ying Zhang; Laurence Florens; Joan W. Conaway; Kausik Si; Robb Krumlauf

    Gene duplication and divergence is a major driver in the emergence of evolutionary novelties. How variations in amino acid sequences lead to loss of ancestral activity and functional diversification of proteins is poorly understood. We used cross-species functional analysis of Drosophila Labial and its mouse HOX1 orthologs (HOXA1, HOXB1, and HOXD1) as a paradigm to address this issue. Mouse HOX1 proteins

    更新日期:2020-12-01
  • Development of specialized sensory neurons engages a nuclear receptor required for functional plasticity
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Mary Rossillo; Niels Ringstad

    During development, the nervous system generates neurons that serve highly specialized roles and, accordingly, possess unique functional attributes. The chemosensory BAG neurons of C. elegans are striking exemplars of this. BAGs sense the respiratory gas carbon dioxide (CO2) and, in a context-dependent manner, switch from mediating avoidance of CO2 to supporting CO2 attraction. To determine mechanisms

    更新日期:2020-12-01
  • The core clock transcription factor BMAL1 drives circadian β-cell proliferation during compensatory regeneration of the endocrine pancreas
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Volodymyr Petrenko; Miri Stolovich-Rain; Bart Vandereycken; Laurianne Giovannoni; Kai-Florian Storch; Yuval Dor; Simona Chera; Charna Dibner

    Circadian clocks in pancreatic islets participate in the regulation of glucose homeostasis. Here we examined the role of these timekeepers in β-cell regeneration after the massive ablation of β cells by doxycycline-induced expression of diphtheria toxin A (DTA) in Insulin-rtTA/TET-DTA mice. Since we crossed reporter genes expressing α- and β-cell-specific fluorescent proteins into these mice, we could

    更新日期:2020-12-01
  • Sexually dimorphic DNA damage responses and mutation avoidance in the mouse germline
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Jordana C. Bloom; John C. Schimenti

    Germ cells specified during fetal development form the foundation of the mammalian germline. These primordial germ cells (PGCs) undergo rapid proliferation, yet the germline is highly refractory to mutation accumulation compared with somatic cells. Importantly, while the presence of endogenous or exogenous DNA damage has the potential to impact PGCs, there is little known about how these cells respond

    更新日期:2020-12-01
  • Replication stress conferred by POT1 dysfunction promotes telomere relocalization to the nuclear pore
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Alexandra M. Pinzaru; Mike Kareh; Noa Lamm; Eros Lazzerini-Denchi; Anthony J. Cesare; Agnel Sfeir

    Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively

    更新日期:2020-12-01
  • Chromosome-autonomous feedback down-regulates meiotic DNA break competence upon synaptonemal complex formation
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Xiaojing Mu; Hajime Murakami; Neeman Mohibullah; Scott Keeney

    The number of DNA double-strand breaks (DSBs) initiating meiotic recombination is elevated in Saccharomyces cerevisiae mutants that are globally defective in forming crossovers and synaptonemal complex (SC), a protein scaffold juxtaposing homologous chromosomes. These mutants thus appear to lack a negative feedback loop that inhibits DSB formation when homologs engage one another. This feedback is

    更新日期:2020-12-01
  • Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Minhong Shen; Yibin Kang

    Metastasis is the ultimate “survival of the fittest” test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms

    更新日期:2020-12-01
  • Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signaling
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Katerina Lawlor; Maria Angeles Marques-Torrejon; Gopuraja Dharmalingham; Yasmine El-Azhar; Michael D. Schneider; Steven M. Pollard; Tristan A. Rodríguez

    There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding

    更新日期:2020-12-01
  • Senescence and the SASP: many therapeutic avenues
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Jodie Birch; Jesús Gil

    Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells

    更新日期:2020-12-01
  • A new role for the synaptonemal complex in the regulation of meiotic recombination
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Nancy M. Hollingsworth

    Proper segregation during meiosis requires that homologs be connected by the combination of crossovers and sister chromatid cohesion. To generate crossovers, numerous double-strand breaks (DSBs) are introduced throughout the genome by the conserved Spo11 endonuclease. DSB formation and its repair are then highly regulated to ensure that homologous chromosomes contain at least one crossover and no DSBs

    更新日期:2020-12-01
  • A window in time for β-cell regeneration
    Genes Dev. (IF 9.527) Pub Date : 2020-12-01
    Benjamin J. Weidemann; Joseph Bass

    In vivo regeneration of β cells provides hope for self-renewal of functional insulin-secreting cells following β-cell failure, a historically fatal condition now sustainable only by administration of exogenous insulin. Despite advances in the treatment of diabetes mellitus, the path toward endogenous renewal of β-cell populations has remained elusive. Intensive efforts have focused on elucidating pancreatic

    更新日期:2020-12-01
  • PRIM1 deficiency causes a distinctive primordial dwarfism syndrome
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    David A. Parry; Lukas Tamayo-Orrego; Paula Carroll; Joseph A. Marsh; Philip Greene; Olga Murina; Carolina Uggenti; Andrea Leitch; The Scottish Genomes Partnership; Rita Káposzta; Gabriella Merő; Andrea Nagy; Brigitta Orlik; Balázs Kovács-Pászthy; Alan J. Quigley; Magdolna Riszter; Julia Rankin; Martin A.M. Reijns; Katalin Szakszon; Andrew P. Jackson; Members of the Scottish Genome Partnership include;

    DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced

    更新日期:2020-11-02
  • The inactive Dnmt3b3 isoform preferentially enhances Dnmt3b-mediated DNA methylation
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Yang Zeng; Ren Ren; Gundeep Kaur; Swanand Hardikar; Zhengzhou Ying; Lance Babcock; Esha Gupta; Xing Zhang; Taiping Chen; Xiaodong Cheng

    The de novo DNA methyltransferases Dnmt3a and Dnmt3b play crucial roles in developmental and cellular processes. Their enzymatic activities are stimulated by a regulatory protein Dnmt3L (Dnmt3-like) in vitro. However, genetic evidence indicates that Dnmt3L functions predominantly as a regulator of Dnmt3a in germ cells. How Dnmt3a and Dnmt3b activities are regulated during embryonic development and

    更新日期:2020-11-02
  • The DNA replication fork suppresses CMG unloading from chromatin before termination.
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    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:2020-11-02
  • A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Ryan Rickels; Lu Wang; Marta Iwanaszko; Patrick A. Ozark; Marc A. Morgan; Andrea Piunti; Natalia Khalatyan; Shimaa H.A. Soliman; Emily J. Rendleman; Jeffrey N. Savas; Edwin R. Smith; Ali Shilatifard

    Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality

    更新日期:2020-11-02
  • EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Senthilkumar Ramamoorthy; Kohei Kometani; Josip S. Herman; Marc Bayer; Sören Boller; Joy Edwards-Hicks; Haribaskar Ramachandran; Rui Li; Ramon Klein-Geltink; Erika L. Pearce; Dominic Grün; Rudolf Grosschedl

    EBF1 and PAX5 mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the Ebf1+/−Pax5+/− (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5

    更新日期:2020-11-02
  • The transcription factor EGR2 is the molecular linchpin connecting STAT6 activation to the late, stable epigenomic program of alternative macrophage polarization
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Bence Daniel; Zsolt Czimmerer; Laszlo Halasz; Pal Boto; Zsuzsanna Kolostyak; Szilard Poliska; Wilhelm K. Berger; Petros Tzerpos; Gergely Nagy; Attila Horvath; György Hajas; Timea Cseh; Aniko Nagy; Sascha Sauer; Jean Francois-Deleuze; Istvan Szatmari; Attila Bacsi; Laszlo Nagy

    Macrophages polarize into functionally distinct subtypes while responding to microenvironmental cues. The identity of proximal transcription factors (TFs) downstream from the polarization signals are known, but their activity is typically transient, failing to explain the long-term, stable epigenomic programs developed. Here, we mapped the early and late epigenomic changes of interleukin-4 (IL-4)-induced

    更新日期:2020-11-02
  • Selective inhibition of CDK7 reveals high-confidence targets and new models for TFIIH function in transcription
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Jenna K. Rimel; Zachary C. Poss; Benjamin Erickson; Zachary L. Maas; Christopher C. Ebmeier; Jared L. Johnson; Tim-Michael Decker; Tomer M. Yaron; Michael J. Bradley; Kristin B. Hamman; Shanhu Hu; Goran Malojcic; Jason J. Marineau; Peter W. White; Martine Brault; Limei Tao; Patrick DeRoy; Christian Clavette; Shraddha Nayak; Leah J. Damon; Ines H. Kaltheuner; Heeyoun Bunch; Lewis C. Cantley; Matthias

    CDK7 associates with the 10-subunit TFIIH complex and regulates transcription by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Few additional CDK7 substrates are known. Here, using the covalent inhibitor SY-351 and quantitative phosphoproteomics, we identified CDK7 kinase substrates in human cells. Among hundreds of high-confidence targets, the vast majority are unique

    更新日期:2020-11-02
  • The many facets of Notch signaling in breast cancer: toward overcoming therapeutic resistance
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Ajeya Nandi; Rumela Chakrabarti

    Breast cancer is the second leading cause of cancer-related death in women and is a complex disease with high intratumoral and intertumoral heterogeneity. Such heterogeneity is a major driving force behind failure of current therapies and development of resistance. Due to the limitations of conventional therapies and inevitable emergence of acquired drug resistance (chemo and endocrine) as well as

    更新日期:2020-11-02
  • p53 directly represses human LINE1 transposons
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Bhavana Tiwari; Amanda E. Jones; Candace J. Caillet; Simanti Das; Stephanie K. Royer; John M. Abrams

    p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5′UTR and stimulating local deposition of

    更新日期:2020-11-02
  • SPRED proteins and their roles in signal transduction, development, and malignancy
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Claire Lorenzo; Frank McCormick

    The roles of SPRED proteins in signaling, development, and cancer are becoming increasingly recognized. SPRED proteins comprise an N-terminal EVH-1 domain, a central c-Kit-binding domain, and C-terminal SROUTY domain. They negatively regulate signaling from tyrosine kinases to the Ras–MAPK pathway. SPRED1 binds directly to both c-KIT and to the RasGAP, neurofibromin, whose function is completely dependent

    更新日期:2020-11-02
  • The alternative macrophage relay: STAT6 passes the baton to EGR2
    Genes Dev. (IF 9.527) Pub Date : 2020-11-01
    Jingwen Liao; Diana C. Hargreaves

    Alternative polarization of macrophages induced by IL-4 is important for homeostasis and tissue repair. Downstream from IL-4 receptor signaling, STAT6 activation is transient, but induces stable transcriptional changes. These data suggest that STAT6 induces second messengers to carry out the alternative transcriptional program. In this issue of Genes & Development, Daniel and colleagues (pp. 1474–1492)

    更新日期:2020-11-02
  • Context-dependent functional compensation between Ythdf m6A reader proteins.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • Break-induced replication promotes fragile telomere formation.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • Yap/Taz promote the scavenging of extracellular nutrients through macropinocytosis.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • AMPK regulation of Raptor and TSC2 mediate metformin effects on transcriptional control of anabolism and inflammation.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • Point-activated ESR1Y541S has a dramatic effect on the development of sexually dimorphic organs.
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    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:2020-10-02
  • The SAGA chromatin-modifying complex: the sum of its parts is greater than the whole
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    Jelly H.M. Soffers; Jerry L. Workman

    There are many large protein complexes involved in transcription in a chromatin context. However, recent studies on the SAGA coactivator complex are generating new paradigms for how the components of these complexes function, both independently and in concert. This review highlights the initial discovery of the canonical SAGA complex 23 years ago, our evolving understanding of its modular structure

    更新日期:2020-10-02
  • A most formidable arsenal: genetic technologies for building a better mouse
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    James F. Clark; Colin J. Dinsmore; Philippe Soriano

    The mouse is one of the most widely used model organisms for genetic study. The tools available to alter the mouse genome have developed over the preceding decades from forward screens to gene targeting in stem cells to the recent influx of CRISPR approaches. In this review, we first consider the history of mice in genetic study, the development of classic approaches to genome modification, and how

    更新日期:2020-10-02
  • Transcriptional activation of macropinocytosis by the Hippo pathway following nutrient limitation
    Genes Dev. (IF 9.527) Pub Date : 2020-10-01
    Sharanya Sivanand; Matthew G. Vander Heiden

    Cancer cells must adapt metabolism to thrive despite nutrient limitations in the tumor microenvironment. In this issue of Genes & Development, King and colleagues (pp. 1345–1358) report a role for transcriptional regulators of the Hippo pathway to facilitate protein scavenging and support proliferation under some nutrient-deprived conditions.

    更新日期:2020-10-02
  • 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