Molecular biology

  • Article
    | Open Access

    Single-cell RNA-seq reveals the cellular heterogeneity in development and disease. Here the authors present a single-nucleus RNA-seq2 that allows deep characterization of nuclei isolated from frozen archived tissues, apply it for transcriptional profiling of individual hepatocytes, and determine a functional crosstalk between liver zonation and ploidy.

    • M. L. Richter
    • , I. K. Deligiannis
    •  & C. P. Martinez-Jimenez
  • Article
    | Open Access

    The Argonaute protein CSR-1 is essential for fertility and viability in C. elegans. Here the authors show that CSR-1A isoform associates preferentially with small RNAs mapping to spermatogenesis-specific genes while CSR-1B isoform binds small RNAs mapping to oogenesis-specific genes. Arginine methylation of CSR-1A promotes small RNA-binding specificity.

    • Dieu An H. Nguyen
    •  & Carolyn M. Phillips
  • Article
    | Open Access

    Mutations in 5’ untranslated regions (UTRs) have a functional role in gene expression in cancer. Here, the authors develop a sequencing-based high throughput functional assay named PLUMAGE and show the effects of these mutations on gene expression and their association with clinical outcomes in prostate cancer.

    • Yiting Lim
    • , Sonali Arora
    •  & Andrew C. Hsieh
  • Article
    | Open Access

    Accurate regulation of protein concentrations according to changes in cell volume that accompany growth and changes in biosynthetic capacity is an important component of cellular homeostasis. Here, using the model organism S. cerevisiae, the authors show how histone production is quantitatively coupled to genome content through the intrinsic properties of histone promoters.

    • Kora-Lee Claude
    • , Daniela Bureik
    •  & Kurt M. Schmoller
  • Article
    | Open Access

    Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.

    • Zhongyuan Bao
    • , Yinlong Liu
    •  & Jing Ji
  • Article
    | Open Access

    Transcriptional state plays a role in genome organization, however factors that link these processes are not well known. Here, the authors show Drosophila transcription factor Motif 1-binding protein (M1BP) interacts with the insulator protein CP190 to promote insulator function and activate Motif 1-dependent transcription at topologically associating domain (TAD) borders.

    • Indira Bag
    • , Shue Chen
    •  & Elissa P. Lei
  • Article
    | Open Access

    It remains unclear how spatial information controls endothelial cell identity and behavior in the developing heart. Here the authors perform single cell RNA sequencing at key developmental timepoints in mice to interrogate cellular contributions to coronary vessel patterning and maturation in the epicardium.

    • Pearl Quijada
    • , Michael A. Trembley
    •  & Eric M. Small
  • Article
    | Open Access

    Osteoarthritis is caused by an imbalance between extracellular matrix synthesis and degradation. Here, the authors show that both strands of microRNA-455, -5p and -3p, target HIF2α and regulate cartilage homeostasis, and show that overexpression of these miRNAs is protective against osteoarthritis in mice.

    • Yoshiaki Ito
    • , Tokio Matsuzaki
    •  & Hiroshi Asahara
  • Article
    | Open Access

    Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.

    • Chi Zhang
    • , Filippo Macchi
    •  & Kirsten C. Sadler
  • Article
    | Open Access

    hNEIL1 (human endonuclease VIII-like 1) is a broadly specific DNA glycosylase for base excision repair. Here, the authors show that hNEIL1 can assume activated or triage conformations: the structural basis for the mechanism that enables broad specificity and reduces futile repair of normal bases.

    • Menghao Liu
    • , Jun Zhang
    •  & Chengqi Yi
  • Article
    | Open Access

    Emerging evidence suggests that exit from pluripotency is a regulated, rather than passive process. Here the authors identify a requirement for SS18-mediated Brg/Brahma-associated factors (BAF) chromatin remodeling complex assembly during exit from pluripotency, and that SS18 promotes BAF assembly through liquidliquid phase separation.

    • Junqi Kuang
    • , Ziwei Zhai
    •  & Duanqing Pei
  • Article
    | Open Access

    Long noncoding RNAs (lncRNAs) are known to regulate the DNA damage response (DDR), however their role in the brain is less well studied. Here, the authors demonstrate a neuron-specific role for Brain Specific DNA-damage Related lncRNA1 (BS-DRL1) and show BS-DRL1 modulates DDR by interacting with HMGB1 in a cell-type specific manner.

    • Min-Min Lou
    • , Xiao-Qiang Tang
    •  & Wen-Yuan Wang
  • Article
    | Open Access

    PARP inhibitors function by trapping PARP1 protein on DNA breaks, which has cytotoxic consequences to cancer cells. Here the authors identify three serine residues within PARP1 as key sites whose efficient HPF1-dependent modification counters PARP1 trapping and contributes to inhibitor tolerance.

    • Evgeniia Prokhorova
    • , Florian Zobel
    •  & Ivan Ahel
  • Article
    | Open Access

    The oncogenic chromatin remodeler ALC1 (amplification in liver cancer 1), also known as CHD1L is an ATP-dependent chromatin remodeler that relaxes chromatin and plays an important role in the poly(ADP-ribose) polymerase 1 -mediated DNA repair pathway. Here, the authors present the ALC1 crystal structure and a cryo-EM structure of ALC1 bound to a nucleosome, which reveal that ALC1 is autoinhibited and how it becomes activated.

    • Li Wang
    • , Kangjing Chen
    •  & Zhucheng Chen
  • Article
    | Open Access

    PIWI protein contains arginine rich motifs that are post-translationally modified to symmetrically methylated arginine (sDMA) residues. Here the authors show that piRNA loading into Aub triggers sDMA modification which is recognized by Krimper to promote formation of Krimper-Aub-Ago3 complex for piRNA amplification in Drosophila.

    • Xiawei Huang
    • , Hongmiao Hu
    •  & Sisi Li
  • Article
    | Open Access

    Mucins play critical roles in maintaining the human microbiome, with their O-glycosylated tandem repeats (TRs) providing important cues for microbiota. Here, the authors develop a cellular platform for producing TRs with defined O-glycan structures to dissect the functions of TR O-glycosylation.

    • Rebecca Nason
    • , Christian Büll
    •  & Yoshiki Narimatsu
  • Article
    | Open Access

    The human DNA primase and DNA polymerase PrimPol replicates through the major oxidative DNA damage lesion 7,8-dihydro-8-oxoguanine (oxoG) via translesion synthesis in a mostly error-free manner thus suppressing oxoG-induced mutagenesis in mitochondria and the nucleus. Here, the authors present crystal structures of PrimPol in complex with an oxoG lesion in different contexts that provide mechanistic insights into how PrimPol performs predominantly accurate synthesis on oxidative-damaged DNAs in human cells.

    • Olga Rechkoblit
    • , Robert E. Johnson
    •  & Aneel K. Aggarwal
  • Article
    | Open Access

    The molecular mechanisms underlying cancer cell radioresistance need to be elucidated. In this study, the authors show that the microRNA biogenesis factor DGCR8 is stabilized by USP51 and ATM upon irradiation and by consequence it promotes the repair of DNA double-strand breaks and radioresistance by recruiting RNF168 to sites of damage.

    • Qinglei Hang
    • , Liyong Zeng
    •  & Li Ma
  • Article
    | Open Access

    Degradation of nonsense mediated mRNA decay (NMD) substrates is carried out by two seemingly independent pathways, SMG6-mediated endonucleolytic cleavage and/or SMG5-SMG7-induced accelerated deadenylation. Here the authors show that SMG5-SMG7 maintain NMD activity by permitting SMG6 activation.

    • Volker Boehm
    • , Sabrina Kueckelmann
    •  & Niels H. Gehring
  • Article
    | Open Access

    The therapeutic application of small interfering RNA (siRNA) is challenging due to its non-specific targeting and delivery issues. Here, the authors report an endogenous micro-RNA guided and hybridisation chain reaction-promoted siRNA delivery system encapsulated in tumour-derived extracellular vesicles, with cancer-specific activation, and achieve silencing of hypoxia-related genes.

    • Xue Gong
    • , Haizhou Wang
    •  & Fuan Wang
  • Article
    | Open Access

    The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

    • Benxia Hu
    • , Hyejung Won
    •  & Daniel H. Geschwind
  • Article
    | Open Access

    Hematopoiesis influences the progression of cardiovascular disease, yet the influence of cardiovascular disease on the bone vasculature is unknown. Hoffmann, Luxán, Abplanalp et al. describe the response of the bone cell composition to myocardial infarction and provide a rationale for using anti-inflammatory therapies to prevent the deterioration of the bone vascular niche

    • Jedrzej Hoffmann
    • , Guillermo Luxán
    •  & Stefanie Dimmeler
  • Article
    | Open Access

    Tpr nucleoporin is known to be essential for nuclear transport and mitosis processes. Here the authors explore the link between Tpr and genome instability providing insights into the role of Tpr in safeguarding cells from RNA-mediated replication stress.

    • Martin Kosar
    • , Michele Giannattasio
    •  & Marco Foiani
  • Article
    | Open Access

    STAT1a is required for pro-inflammatory responses in macrophages. Here the authors reveal that post-translational modification of STAT1a, ADPribosylation, plays a critical role in enhancer formation and activation, thus modulating IFNγ-stimulated inflammatory responses in macrophages.

    • Rebecca Gupte
    • , Tulip Nandu
    •  & W. Lee Kraus
  • Article
    | Open Access

    ATRX is a chromatin remodeling protein, which loss has been associated to replication stress, DNA damage, and DNA repair failures that drive genome instability. Here the authors reveal that ATRX protects genomic integrity at G4-containing regions by maintaining these regions in a closed heterochromatic state.

    • Yu-Ching Teng
    • , Aishwarya Sundaresan
    •  & Laura A. Banaszynski
  • Article
    | Open Access

    Citrullination is a posttranslational modification of arginines. Here, the authors show that HCMV infection increases citrullination of host and virus proteins to promote infection and that citrullinated interferon-inducible protein IFIT1 is impaired in RNA binding, as a potential mechanism of evasion.

    • Gloria Griffante
    • , Francesca Gugliesi
    •  & Santo Landolfo
  • Article
    | Open Access

    Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.

    • Matthew D. Young
    • , Thomas J. Mitchell
    •  & Sam Behjati
  • Article
    | Open Access

    Whether the adult testis harbours a somatic progenitor population is unknown. Here, the authors provide evidence that the testis interstitial cells expressing the transcription factor Tcf21 maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury.

    • Yu-chi Shen
    • , Adrienne Niederriter Shami
    •  & Saher Sue Hammoud
  • Article
    | Open Access

    How gene expression reactivation is promoted following DNA damage is not yet clear. Here, the authors identify a role for the human histone chaperone complex HIRA in transcription restart following UV damage independently of its function in new H3.3 histone deposition.

    • Déborah Bouvier
    • , Juliette Ferrand
    •  & Sophie E. Polo
  • Article
    | Open Access

    Single-stranded DNA during DNA replication and repair in S/G2 needs protection by replication protein A (RPA). Here the authors reveal that RPA also shields inherited single-stranded DNA in G1, representing replication remnants from the previous cell cycle, to allow for post-mitotic DNA synthesis.

    • Aleksandra Lezaja
    • , Andreas Panagopoulos
    •  & Matthias Altmeyer
  • Article
    | Open Access

    Here, the authors report de novo design, optimization and characterization of tRNAs that decode UGA stop codons in E. coli. The structure of the ribosome in a complex with the designed tRNA bound to a UGA stop codon suggests that distinct A-site ligands (tRNAs versus release factors) induce distinct conformation of the stop codon within the mRNA in the decoding center.

    • Suki Albers
    • , Bertrand Beckert
    •  & Zoya Ignatova
  • Article
    | Open Access

    Telomeres suppress the DNA damage response at chromosome ends. Here the authors show that in budding yeast the activity of the MRX complex in DNA repair and DNA damage signaling is inhibited by telomeric protein Rif2 via a short motif at the N-terminus.

    • Freddy Khayat
    • , Elda Cannavo
    •  & Alessandro Bianchi
  • Article
    | Open Access

    R loops are formed when single-stranded RNA anneals to one strand of DNA, forming three-stranded structures containing DNA-RNA hybrids and the displaced non-template single-stranded DNA. Here the authors reveal that the DNA:RNA helicase UPF1 plays a role in promoting R loops formation at telomeric double strand breaks to stimulate DNA resection and repair.

    • Greg H. P. Ngo
    • , Julia W. Grimstead
    •  & Duncan M. Baird
  • Article
    | Open Access

    In most mammals, imprinted genes contain epigenetic marks that differ in each parental genome and control their parent-of-origin-specific expression. Here, the authors map imprinted genes in mouse preimplantation embryos and find that imprinted gene expression in blastocysts is mainly dependent on Polycomb-mediated H3K27me3-associated gene silencing.

    • Laura Santini
    • , Florian Halbritter
    •  & Martin Leeb
  • Article
    | Open Access

    The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.

    • Wei Wang
    • , Fei Shao
    •  & Zhimin Lu
  • Article
    | Open Access

    Many proteins exist in various proteoforms but detecting these variants by bottom-up proteomics remains difficult. Here, the authors present a computational approach based on peptide correlation analysis to identify and characterize proteoforms from bottom-up proteomics data.

    • Isabell Bludau
    • , Max Frank
    •  & Ruedi Aebersold