Molecular biology

  • Article
    | Open Access

    Abdominal aortic aneurysm (AAA) is a potentially fatal and often asymptomatic disease whose causes remain unclear. Here the authors show that a microRNA, miR-24, and its target, the glycoprotein chitinase 3-like 1, represent key regulators of AAA development.

    • Lars Maegdefessel
    • , Joshua M. Spin
    •  & Philip S. Tsao
  • Article |

    MicroRNAs play important roles in the maintenance of cellular homeostasis through the post-transcriptional regulation of gene expression. Here, the authors implicate loss of the miRNA biogenesis factor Drosha and altered miRNA maturation in tumour progression under hypoxic conditions.

    • Rajesha Rupaimoole
    • , Sherry Y. Wu
    •  & Anil K. Sood
  • Article |

    Reduced expression of DICER—responsible for the processing of microRNA precursors—was previously linked to poor clinical outcomes in cancer patients. Here, the authors uncover an epigenetic mechanism by which hypoxia suppresses DICER expression and deregulates the miR-200-Zeb1 circuit in breast cancer to promote the tumour phenotype.

    • Twan van den Beucken
    • , Elizabeth Koch
    •  & Bradly G. Wouters
  • Article
    | Open Access

    DNA methylation is essential for proper gene expression, development and genome stability. Here the authors present whole-genome DNA methylation analyses of purified mouse cardiomyocytes from newborn, adult and failing hearts and find highly dynamic patterns between the three phenotypes of cardiomyocytes.

    • Ralf Gilsbach
    • , Sebastian Preissl
    •  & Lutz Hein
  • Article
    | Open Access

    A subset of cancers maintains telomere length independently of telomerase by activating alternative lengthening of telomeres (ALT) pathways. Here the authors show that RNaseH1 modulates telomeric homologous recombination frequencies in ALT cells by regulating the levels of RNA–DNA hybrids between TERRA and telomeric DNA.

    • Rajika Arora
    • , Yongwoo Lee
    •  & Claus M. Azzalin
  • Article |

    Cyclodipeptide synthases hijack aminoacyl tRNAs to produce various cyclic dipeptides—the biosynthetic precursors of several secondary metabolites. Here, the authors solved the crystal structure of a cyclodipeptide synthase bound to a reaction intermediate analogue and provide novel insights into the mechanism of synthesis.

    • Mireille Moutiez
    • , Emmanuelle Schmitt
    •  & Muriel Gondry
  • Article
    | Open Access

    The scaffold protein Abraxas brother 1 (ABRO1) accumulates in the nucleus after oxidative stress but its role in cellular responses to DNA damage has not been elucidated. Here the authors show that ABRO1 exerts its tumour suppressor activity by regulating p53 stability via USP7 deubiquitinase.

    • Jianhong Zhang
    • , Mengmeng Cao
    •  & Xiaoming Yang
  • Article
    | Open Access

    Post-translational mRNA editing has the potential to enhance the diversity of gene products and alter the functional properties of proteins. Here, Li et al. provide evidence that RNA editing is involved in generating caste-specific contrasting phenotypes in the leaf-cutting ant Acromyrmex echinatior.

    • Qiye Li
    • , Zongji Wang
    •  & Guojie Zhang
  • Article |

    Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies but little is known about the physiological function of this domain. Here the authors show that phosphoinositide binding to TRPV4 ARD leads to suppression of the channel activity, and obtain the crystal structure of the domain in complex with inositol-1,4,5-trisphosphate.

    • Nobuaki Takahashi
    • , Sayaka Hamada-Nakahara
    •  & Shiro Suetsugu
  • Article |

    The enzymes Sae2 and Sgs1 regulate telomere maintenance in yeast cells that are telomerase-positive or -negative, but how they do this is unclear. Here the authors show that Sae2 and Sgs1 facilitate telomere replication in telomerase-positive cells, but generate single-stranded DNA at eroded telomeres in telomerase-negative cells.

    • Julien Hardy
    • , Dmitri Churikov
    •  & Marie-Noëlle Simon
  • Article |

    The essential nature of replicative polymerases has hampered the study of polymerase-δ mutations found in colorectal cancer cells. Here, using polymerase-δ mutations as a proof of principle, the authors present an inducible single vector system that replaces any endogenous gene with an RNAi-resistant mutant version.

    • Medini Manohar Ghodgaonkar
    • , Patrick Kehl
    •  & Josef Jiricny
  • Article
    | Open Access

    Shortened telomeres and reduced mitochondrial biogenesis are cellular hallmarks of ageing. Here, Missios et al.show that old mice with telomere dysfunction have an increased energetic demand that cannot be met unless mice are fed a glucose-rich diet, which improves energy metabolism and extends lifespan.

    • Pavlos Missios
    • , Yuan Zhou
    •  & K. Lenhard Rudolph
  • Article
    | Open Access

    Aberrant function of the extracellular matrix receptor dystroglycan is associated with human congenital muscular dystrophies, often associated with brain and eye abnormalities. Here, the authors describe a role for the miRNA miR-310s in regulating dystroglycan expression during Drosophilabrain development.

    • Andriy S. Yatsenko
    • , April K. Marrone
    •  & Halyna R. Shcherbata
  • Article |

    miRNAs regulate a range of biological processes, including the immune response and viral infection. Here, the authors perform a genome-wide miRNA mimic screen and identify a miRNA induced by IRF3 during viral infection that regulates viral–host interactions.

    • Melanie L. Yarbrough
    • , Ke Zhang
    •  & Beatriz M. A. Fontoura
  • Article
    | Open Access

    RNA binding proteins are key regulators of alternative splicing. Here, Best et al. show that the human Tra2α and Tra2ß RNA binding proteins jointly contribute to the control of constitutive and alternative splicing events to regulate essential biological processes including the response to DNA damage.

    • Andrew Best
    • , Katherine James
    •  & David J. Elliott
  • Article
    | Open Access

    The human Holliday junction resolvase GEN1 functions during anaphase to eliminate recombination intermediates that block proper chromosome segregation. Here, the authors demonstrate that GEN1 activity is regulated independently of its phosphorylation status and relies on its active exclusion from the nucleus.

    • Ying Wai Chan
    •  & Stephen C. West
  • Article |

    X-chromosome inactivation is a tightly regulated mechanism, which silences one of the two female X chromosomes. Here Makhlouf et al. show that the autosomal transcription factor YY1 directly promotes expression of the XistRNA—a master regulator of X-chromosome inactivation—at the onset of the inactivation process.

    • Mélanie Makhlouf
    • , Jean-François Ouimette
    •  & Claire Rougeulle
  • Article |

    Subtilase SUB1, a proteolytic enzyme required for the exit of malarial parasites from host cells, represents a promising target for anti-malarial drugs. Here, Giganti et al. report the structure of PlasmodiumSUB1 and identify an essential domain involved in calcium-dependent activation of the enzyme.

    • David Giganti
    • , Anthony Bouillon
    •  & Jean-Christophe Barale
  • Article |

    Trisomy 12 is the most frequent chromosomal abnormality detected in cultures of human pluripotent stem cells. Here the authors show that human pluripotent stem cells carrying this abnormality exhibit gene expression profiles more similar to those of germ cell tumours, and give rise to more aggressive teratomas.

    • Uri Ben-David
    • , Gal Arad
    •  & Juan Carlos Biancotti
  • Article
    | Open Access

    Chronic infection with the bacterium Helicobacter pylori is associated with inflammation and increased risk of gastric cancer. Kiga et al. show that methylation and silencing of the microRNA gene miR-210is associated with infection in humans, and promotes proliferation of gastric epithelial cells in culture.

    • Kotaro Kiga
    • , Hitomi Mimuro
    •  & Chihiro Sasakawa
  • Article |

    Hoogsteen (HG) base pairs occur transiently within DNA and exhibit altered non Watson–Crick (WC)-pairing geometries with the potential to govern sequence-dependent DNA processes. Here, Alvey et al.show that HG base pairing occurs within diverse sequence contexts and define the energetic landscapes that favour WC-to-HG transitions.

    • Heidi S. Alvey
    • , Federico L. Gottardo
    •  & Hashim M. Al-Hashimi
  • Article
    | Open Access

    Telomeric RNAs (TERRAs) are known to be transcribed towards the telomere from subtelomeric regions, however, their precise genomic origins are unclear. Here López de Silanes et al.identify novel transcripts that originate from the subtelomeric region of mouse chromosome 18 and behave as bona fide TERRAs.

    • Isabel López de Silanes
    • , Osvaldo Graña
    •  & Maria A Blasco
  • Article
    | Open Access

    Dose escalation in antigen-specific therapies is recognized as safe and effective, but the underlying effects of dosing variables on the immune system are not understood. Here, the authors demonstrate that dose escalation causes sequential modulation of gene expression among antigen-specific lymphocytes.

    • Bronwen R. Burton
    • , Graham J. Britton
    •  & David C. Wraith
  • Article |

    The inherent inaccuracy of viral RNA polymerases promotes viral evolution, but the importance of viral genetic diversity during infection is unclear. Here, Cheung et al.show that influenza strains with enhanced polymerase fidelity and low mutational frequency display reduced pathogenicity in mice.

    • Peter P. H. Cheung
    • , Simon J. Watson
    •  & Hui-Ling Yen
  • Article |

    The quantitative relationship between the fluctuation of specific extrinsic and intrinsic factors, and stochastic fluctuations in gene expression - or noise - has not been clearly established. Here, Yang et al.demonstrate that intrinsic noise is independent of - while extrinsic noise scales linearly with - variation in RNA polymerase abundance.

    • Sora Yang
    • , Seunghyeon Kim
    •  & Nam Ki Lee
  • Article |

    Heterochromatin is a ‘repressed’ chromatin state involved in the generation of centromeres, the protection of telomeres and the maintenance of genome integrity. Here Swygert et al.show that Sir3 - a key factor in the formation of heterochromatin - promotes a chromatin structure distinct from the canonical 30 nm fibre.

    • Sarah G. Swygert
    • , Benjamin J. Manning
    •  & Craig L. Peterson
  • Article |

    The process that balances expression of X-chromosomal genes between males and females is under tight regulatory control. Here, Militti et al. show that in Drosophila, the RNA-binding protein UNR functions during dosage compensation to promote the interaction between the RNA helicase MLE and the long non-coding RNA roX2.

    • Cristina Militti
    • , Sylvain Maenner
    •  & Fátima Gebauer
  • Article
    | Open Access

    Changes in chromatin structure impact gene expression programs by modulating accessibility to the transcription machinery. Here, West et al. explore differences in nucleosome occupancy between mammalian pluripotent and somatic cells and uncover regulatory regions likely to play key roles in determining cell identity.

    • Jason A. West
    • , April Cook
    •  & Robert E. Kingston
  • Article
    | Open Access

    Common methods to detect adenosine-to-inosine RNA editing sites rely on mapping short RNA reads to the genome while allowing only a limited number of mismatches. Here, Porath et al. present a novel RNA-seq based approach to identify hyper-edited reads that significantly expands the RNA editome.

    • Hagit T. Porath
    • , Shai Carmi
    •  & Erez Y. Levanon
  • Article |

    Tumour suppressor activity of p53 has been suggested to rely on acetylation of its C terminus. Here Wang and colleagues show that the Rho GTPase-activating protein ArhGAP30 is required for P300-mediated p53 acetylation and functional activation in colorectal cancer, and identify ArhGAP30 as a potential prognostic marker.

    • Jilin Wang
    • , Jin Qian
    •  & Jing-Yuan Fang
  • Article |

    Brown fat tissue contributes to organismal energy expenditure due to its thermogenic capacity. Here, the authors identify miR-378 as a specific regulator of brown fat tissue expansion, and suggest that physiological crosstalk between adipose tissue depots leads to a reduction in white fat mass.

    • Dongning Pan
    • , Chunxiao Mao
    •  & Yong-Xu Wang
  • Article
    | Open Access

    RNA sequencing has enabled the global analysis of both gene expression levels and splicing events. Here, the authors develop a multivariate approach that is able to identify SNPs that influence splicing, and investigate the overlap of these with functional domains across the genome, including previously identified GWAS signals.

    • Jean Monlong
    • , Miquel Calvo
    •  & Roderic Guigó
  • Article
    | Open Access

    Identifying miRNA response elements (MREs) within target mRNAs can be done computationally but the functional validation of putative MREs remains challenging. Here, Bassett et al. describe applications of genome engineering to target and assess the functional significance of MREs in different organisms and stages of development.

    • Andrew R. Bassett
    • , Ghows Azzam
    •  & Tudor A. Fulga
  • Article
    | Open Access

    Myc has been implicated in the development of multiple types of cancer. Here, the authors explore the therapeutic potential and mechanism of action of Myc inhibition in mouse and human models of glioblastoma, an aggressive type of tumour that is often resistant to conventional therapy.

    • Daniela Annibali
    • , Jonathan R. Whitfield
    •  & Laura Soucek
  • Article |

    Skeletal muscle stem cells are in a state of cell cycle arrest in adult skeletal muscles and are stimulated to proliferate and differentiate in response to injury or pathology. Here the authors identify two microRNAs, miR-195 and miR-497, which induce cell cycle arrest in the stem cells and suppress myogenesis.

    • Takahiko Sato
    • , Takuya Yamamoto
    •  & Atsuko Sehara-Fujisawa
  • Article
    | Open Access

    The process of controlled chromatin release from the nuclei of inflammatory cells to entrap and kill bacteria, termed ETosis, is important in innate immunity in vertebrates. Here the authors demonstrate that ETosis, mediated by hematocytes, also contributes to defence mechanisms in invertebrates.

    • Calum T. Robb
    • , Elisabeth A. Dyrynda
    •  & Valerie J. Smith