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Genes & Development

Oleksandr Dergai, Pascal Cousin, Jerome Gouge, Karishma Satia, Viviane Praz, Tracy Kuhlman, Philippe Lhôte, Alessandro Vannini, Nouria Hernandez
RNA polymerase II (Pol II) small nuclear RNA (snRNA) promoters and type 3 Pol III promoters have highly similar structures; both contain an interchangeable enhancer and "proximal sequence element" (PSE), which recruits the SNAP complex (SNAPc). The main distinguishing feature is the presence, in the type 3 promoters only, of a TATA box, which determines Pol III specificity. To understand the mechanism by which the absence or presence of a TATA box results in specific Pol recruitment, we examined how SNAPc and general transcription factors required for Pol II or Pol III transcription of SNAPc-dependent genes (i...
May 21, 2018: Genes & Development
Yashpal Rawal, Răzvan V Chereji, Hongfang Qiu, Sudha Ananthakrishnan, Chhabi K Govind, David J Clark, Alan G Hinnebusch
The nucleosome remodeling complex RSC functions throughout the yeast genome to set the positions of -1 and +1 nucleosomes and thereby determines the widths of nucleosome-depleted regions (NDRs). The related complex SWI/SNF participates in nucleosome remodeling/eviction and promoter activation at certain yeast genes, including those activated by transcription factor Gcn4, but did not appear to function broadly in establishing NDRs. By analyzing the large cohort of Gcn4-induced genes in mutants lacking the catalytic subunits of SWI/SNF or RSC, we uncovered cooperation between these remodelers in evicting nucleosomes from different locations in the promoter and repositioning the +1 nucleosome downstream to produce wider NDRs-highly depleted of nucleosomes-during transcriptional activation...
May 21, 2018: Genes & Development
Chuan Huang, Dongming Liang, Deirdre C Tatomer, Jeremy E Wilusz
Circular RNAs (circRNAs) are generated from many protein-coding genes. Most accumulate in the cytoplasm, but how circRNA localization or nuclear export is controlled remains unclear. Using RNAi screening, we found that depletion of the Drosophila DExH/D-box helicase Hel25E results in nuclear accumulation of long (>800-nucleotide), but not short, circRNAs. The human homologs of Hel25E similarly regulate circRNA localization, as depletion of UAP56 (DDX39B) or URH49 (DDX39A) causes long and short circRNAs, respectively, to become enriched in the nucleus...
May 17, 2018: Genes & Development
Wareed Ahmed, Joachim Lingner
Telomerase counteracts telomere shortening and cellular senescence in germ, stem, and cancer cells by adding repetitive DNA sequences to the ends of chromosomes. Telomeres are susceptible to damage by reactive oxygen species (ROS), but the consequences of oxidation of telomeres on telomere length and the mechanisms that protect from ROS-mediated telomere damage are not well understood. In particular, 8-oxoguanine nucleotides at 3' ends of telomeric substrates inhibit telomerase in vitro, whereas, at internal positions, they suppress G-quadruplex formation and were therefore proposed to promote telomerase activity...
May 17, 2018: Genes & Development
Rhea R Datta, Jia Ling, Jesse Kurland, Xiaotong Ren, Zhe Xu, Gozde Yucel, Jackie Moore, Leila Shokri, Isabel Baker, Timothy Bishop, Paolo Struffi, Rimma Levina, Martha L Bulyk, Robert J Johnston, Stephen Small
The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster , another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown...
May 15, 2018: Genes & Development
Jia Fei, Haruhiko Ishii, Marten A Hoeksema, Franz Meitinger, George A Kassavetis, Christopher K Glass, Bing Ren, James T Kadonaga
Our understanding of transcription by RNA polymerase II (Pol II) is limited by our knowledge of the factors that mediate this critically important process. Here we describe the identification of NDF, a nucleosome-destabilizing factor that facilitates Pol II transcription in chromatin. NDF has a PWWP motif, interacts with nucleosomes near the dyad, destabilizes nucleosomes in an ATP-independent manner, and facilitates transcription by Pol II through nucleosomes in a purified and defined transcription system as well as in cell nuclei...
May 14, 2018: Genes & Development
Minchul Kim, Hagen Wende, Jan Walcher, Johannes Küehnemund, Cyril Cheret, Stefan Kempa, Erik McShane, Matthias Selbach, Gary R Lewin, Carmen Birchmeier
Cholesterol is a major constituent of myelin membranes, which insulate axons and allow saltatory conduction. Therefore, Schwann cells, the myelinating glia of the peripheral nervous system, need to produce large amounts of cholesterol. Here, we define a crucial role of the transcription factor Maf in myelination and cholesterol biosynthesis and show that Maf acts downstream from Neuregulin1 (Nrg1). Maf expression is induced when Schwann cells begin myelination. Genetic ablation of Maf resulted in hypomyelination that resembled mice with defective Nrg1 signaling...
May 10, 2018: Genes & Development
Martin A Newman, Fei Ji, Sylvia E J Fischer, Anthony Anselmo, Ruslan I Sadreyev, Gary Ruvkun
RNAi pathways detect and silence foreign nucleic acids such as viruses as well as endogenous genes in many species. The phylogenetic profile across eukaryotes of proteins that mediate key steps in RNAi is correlated with the profiles of multiple mRNA splicing proteins and with intron number, suggesting that RNAi may surveil mRNA splicing to detect the divergent or absent introns of viruses. Here we examine the role of mRNA splicing in Caenorhabditis elegans RNAi . We found that viable null mutations in U1 and U2 small nuclear ribonucleic protein (snRNP)-specific splicing factor genes cause defects in RNAi...
May 8, 2018: Genes & Development
Joyce V Lee, Corbett T Berry, Karla Kim, Payel Sen, Taehyong Kim, Alessandro Carrer, Sophie Trefely, Steven Zhao, Sully Fernandez, Lauren E Barney, Alyssa D Schwartz, Shelly R Peyton, Nathaniel W Snyder, Shelley L Berger, Bruce D Freedman, Kathryn E Wellen
The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes...
April 19, 2018: Genes & Development
Jose Mario Bello Pineda, Robert K Bradley
Although branchpoint recognition is an essential component of intron excision during the RNA splicing process, the branchpoint itself is frequently assumed to be a basal, rather than regulatory, sequence feature. However, this assumption has not been systematically tested due to the technical difficulty of identifying branchpoints and quantifying their usage. Here, we analyzed ∼1.31 trillion reads from 17,164 RNA sequencing data sets to demonstrate that almost all human introns contain multiple branchpoints...
April 17, 2018: Genes & Development
Martina Begnis, Manasi S Apte, Hirohisa Masuda, Devanshi Jain, David Lee Wheeler, Julia Promisel Cooper
The identification of telomerase-negative HAATI (heterochromatin amplification-mediated and telomerase-independent) cells, in which telomeres are superseded by nontelomeric heterochromatin tracts, challenged the idea that canonical telomeres are essential for chromosome linearity and raised crucial questions as to how such tracts translocate to eroding chromosome ends and confer end protection. Here we show that HAATI arises when telomere loss triggers a newly recognized illegitimate translocation pathway that requires RNAi factors...
April 13, 2018: Genes & Development
Hana Cho, Xavier Rambout, Michael L Gleghorn, Phuong Quoc Thuc Nguyen, Christopher R Phipps, Keita Miyoshi, Jason R Myers, Naoyuki Kataoka, Rudi Fasan, Lynne E Maquat
Although peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a well-established transcriptional coactivator for the metabolic adaptation of mammalian cells to diverse physiological stresses, the molecular mechanism by which it functions is incompletely understood. Here we used in vitro binding assays, X-ray crystallography, and immunoprecipitations of mouse myoblast cell lysates to define a previously unknown cap-binding protein 80 (CBP80)-binding motif (CBM) in the C terminus of PGC-1α...
April 13, 2018: Genes & Development
Cristina Mayor-Ruiz, Teresa Olbrich, Matthias Drosten, Emilio Lecona, Maria Vega-Sendino, Sagrario Ortega, Orlando Dominguez, Mariano Barbacid, Sergio Ruiz, Oscar Fernandez-Capetillo
MEK inhibition in combination with a glycogen synthase kinase-3β (GSK3β) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets...
April 12, 2018: Genes & Development
Carlos Mendez-Dorantes, Ragini Bhargava, Jeremy M Stark
Chromosomal deletion rearrangements mediated by repetitive elements often involve repeats separated by several kilobases and sequences that are divergent. While such rearrangements are likely induced by DNA double-strand breaks (DSBs), it has been unclear how the proximity of DSBs relative to repeat sequences affects the frequency of such events. We generated a reporter assay in mouse cells for a deletion rearrangement involving repeats separated by 0.4 Mb. We induced this repeat-mediated deletion (RMD) rearrangement with two DSBs: the 5' DSB that is just downstream from the first repeat and the 3' DSB that is varying distances upstream of the second repeat...
April 10, 2018: Genes & Development
Yuan Pan, Min Xiong, Ran Chen, Yu Ma, Courtney Corman, Meron Maricos, Urs Kindler, Marcus Semtner, Yi-Hsien Chen, Sonika Dahiya, David H Gutmann
Pediatric low-grade gliomas (LGGs) frequently do not engraft in immunocompromised mice, limiting their use as an experimental platform. In contrast, murine Neurofibromatosis-1 ( Nf1 ) optic LGG stem cells (o-GSCs) form glioma-like lesions in wild-type, but not athymic, mice following transplantation. Here, we show that the inability of athymic mice to support o-GSC engraftment results from impaired microglia/macrophage function, including reduced expression of Ccr2 and Ccl5, both of which are required for o-GSC engraftment and Nf1 optic glioma growth...
April 9, 2018: Genes & Development
Mickaël Ohanna, Mickaël Cerezo, Nicolas Nottet, Karine Bille, Robin Didier, Guillaume Beranger, Baharia Mograbi, Stéphane Rocchi, Laurent Yvan-Charvet, Robert Ballotti, Corine Bertolotto
In BRAFV600E melanoma cells, a global metabolomic analysis discloses a decrease in nicotinamide adenine dinucleotide (NAD+ ) levels upon PLX4032 treatment that is conveyed by a STAT5 inhibition and a transcriptional regulation of the nicotinamide phosphoribosyltransferase (NAMPT) gene. NAMPT inhibition decreases melanoma cell proliferation both in vitro and in vivo, while forced NAMPT expression renders melanoma cells resistant to PLX4032. NAMPT expression induces transcriptomic and epigenetic reshufflings that steer melanoma cells toward an invasive phenotype associated with resistance to targeted therapies and immunotherapies...
March 22, 2018: Genes & Development
Masanari Seike, Yoshiki Omatsu, Hitomi Watanabe, Gen Kondoh, Takashi Nagasawa
Bone marrow is the tissue filling the space between bone surfaces. Hematopoietic stem cells (HSCs) are maintained by special microenvironments known as niches within bone marrow cavities. Mesenchymal cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells or leptin receptor-positive (LepR+ ) cells, are a major cellular component of HSC niches that gives rise to osteoblasts in bone marrow. However, it remains unclear how osteogenesis is prevented in most CAR/LepR+ cells to maintain HSC niches and marrow cavities...
March 21, 2018: Genes & Development
Laura DeVault, Tun Li, Sarah Izabel, Katherine L Thompson-Peer, Lily Yeh Jan, Yuh Nung Jan
Dendrites possess distinct structural and functional properties that enable neurons to receive information from the environment as well as other neurons. Despite their key role in neuronal function, current understanding of the ability of neurons to regenerate dendrites is lacking. This study characterizes the structural and functional capacity for dendrite regeneration in vivo in adult animals and examines the effect of neuronal maturation on dendrite regeneration. We focused on the class IV dendritic arborization (c4da) neuron of the Drosophila sensory system, which has a dendritic arbor that undergoes dramatic remodeling during the first 3 d of adult life and then maintains a relatively stable morphology thereafter...
March 21, 2018: Genes & Development
Jacinthe Azevedo, Damien Garcia, Dominique Pontier, Stephanie Ohnesorge, Agnes Yu, Shahinez Garcia, Laurence Braun, Marc Bergdoll, Mohamed Ali Hakimi, Thierry Lagrange, Olivier Voinnet
No abstract text is available yet for this article.
April 1, 2018: Genes & Development
Tassa Saldi, Nova Fong, David L Bentley
No abstract text is available yet for this article.
April 1, 2018: Genes & Development
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