() is the causative agent of tuberculosis, one of the deadliest infectious diseases worldwide. Previous studies have established that synonymous recoding to introduce rare codon pairings can attenuate viral pathogens. We hypothesized that non-optimal codon pairing could be an effective strategy for attenuating gene expression to create a live vaccine for . We instead discovered that these synonymous changes enabled the transcription of functional mRNA that initiated in the middle of the open reading frame and from which many smaller protein products were expressed. To our knowledge, this is one of the first reports that synonymous recoding of a gene in any organism can create or induce intragenic transcription start sites.
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http://dx.doi.org/10.1128/mbio.00841-23 | DOI Listing |
J Med Genet
December 2024
Revvity Omics, Waltham, Massachusetts, USA
Background: Pathogenic variants in the gene are associated with dystrophinopathy including Duchenne and Becker muscular dystrophy (DMD/BMD). Targeted gene, gene panels, exomes and genome sequencing have advanced genetic diagnostics, yet some cases remain elusive.
Methods: We performed total RNA sequencing (RNAseq) on muscle biopsy from 13 male patients with a clinical diagnosis of DMD/BMD.
Nucleic Acids Res
December 2024
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
Transcription of transfer RNA (tRNA) genes by RNA polymerase (Pol) III requires the general transcription factor IIIC (TFIIIC), which recognizes intragenic A-box and B-box DNA motifs of type II gene promoters. However, the underlying mechanism has remained elusive, in part due to missing structural information for A-box recognition. In this study, we use single-particle cryogenic electron microscopy (cryo-EM) and single-molecule fluorescence resonance energy transfer (smFRET) to reveal structural and real-time kinetic insights into how the 520-kDa yeast TFIIIC complex engages A-box and B-box DNA motifs in the context of a tRNA gene promoter.
View Article and Find Full Text PDFNat Neurosci
November 2024
Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
Mutations in methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome. MeCP2 is thought to regulate gene transcription by binding to methylated DNA broadly across the genome. Here, using cleavage under target and release under nuclease (CUT&RUN) assays in the adult mouse cortex, we show that MeCP2 strongly binds to specific gene enhancers that we call MeCP2-binding hotspots (MBHs).
View Article and Find Full Text PDFGenomics
November 2024
Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; School of Life Sciences, University of Nevada Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154, USA; Heligenics Inc., 10530 Discovery Drive, Las Vegas, NV 89135, USA. Electronic address:
Many pathological conditions are a result of intragenic epistasis; however, there are ambiguities in current epistasis models. Herein, the new Mutation Interaction Spectrum model defines a discrete outcome, named a Mutation Interaction, for each double point mutation in a gene and its component single mutations. The model is a universal genetic model of all types of mutation interactions and their functional outcomes and is derived from digital logic, commonly used in electrical engineering.
View Article and Find Full Text PDFFront Genet
November 2024
Department of Pharmacology and Physiology, Unit of Clinical Genetics and Functional Genomics, School of Medicine, University of Zaragoza, CIBERER-GCV02 and IIS-Aragon, Zaragoza, Spain.
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