Anderson, Stephen J

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2016 - 20192
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  • Publication
    Post-Transcriptional Regulation Of The Eulkaryotic Transcriptome By The Covalent Rna Modicication N6-Methyladenosine
    (2019-01-01) Anderson, Stephen J
    Post-Transcriptional regulation of the eukaryotic transcriptome by the covalent RNA modification N6-methyladenosine Stephen James Anderson Brian Gregory Once a messenger RNA molecule is transcribed, a myriad of RNA fate decisions must be made. How these fate decisions are made is often unclear, and elucidating factors determining these fate outcomes is an essential task in order to fully understand gene regulation. One poorly- understood but undoubtedly important factor in post-transcriptional gene regulation is the covalent modification of ribonucleotides. Much like DNA can have chemical groups added to a nucleotide within its primary sequence, RNA can be modified in a similar manner. These covalent modifications of RNA are a ubiquitous feature found within the RNA of all organisms. Dozens of these modifications have been described to date, yet the function or importance of most of these modifications remains unclear. One crucial RNA modification is N6-methyladenosine (m6A), as it is the most abundant known non-cap modification within the eukaryotic transcriptome. In this work, we characterize the role of m6A in the Arabidopsis transcriptome using various sequencing methods that demonstrate that m6A is an abundant mark that is largely maintained across differing Arabidopsis tissues and developmental stages. This prevalent mark promotes transcript stability in mNRAs involved in many important and diverse biological processes, such as salt stress. The absence of this mark results in endonucleolytic cleavage and degradation of the transcript in a highly specific and local manner. We further demonstrate that this modification modulates secondary structure throughout the transcriptome, and that m6A is associated with changes in RNA-binding protein association. Lastly, we turn our view to how an association between m6A and the m6A-specific binding protein YTHDC1 influences the development and transcriptome-wide splicing and polyadenylation pattern in the mouse germline. We demonstrate that in the absence of YTHDC1, widespread developmental, splicing, and polyadenylation defects occur, resulting in non-functional gametes. In total, this work greatly expands our knowledge and understanding of the biological importance and mechanisms of m6A-mediated post-transcriptional regulation.
  • Publication
    Genome-Wide Mapping of Uncapped and Cleaved Transcripts Reveals a Role for the Nuclear mRNA Cap-Binding Complex in Cotranslational RNA Decay in Arabidopsis
    (2016-10-01) Yu, Xiang; Anderson, Stephen J; Gregory, Brian D; Willmann, Matthew R
    RNA turnover is necessary for controlling proper mRNA levels posttranscriptionally. In general, RNA degradation is via exoribonucleases that degrade RNA either from the 5′ end to the 3′ end, such as XRN4, or in the opposite direction by the multisubunit exosome complex. Here, we use genome-wide mapping of uncapped and cleaved transcripts to reveal the global landscape of cotranslational mRNA decay in the Arabidopsis thaliana transcriptome. We found that this process leaves a clear three nucleotide periodicity in open reading frames. This pattern of cotranslational degradation is especially evident near the ends of open reading frames, where we observe accumulation of cleavage events focused 16 to 17 nucleotides upstream of the stop codon because of ribosomal pausing during translation termination. Following treatment of Arabidopsis plants with the translation inhibitor cycloheximide, cleavage events accumulate 13 to 14 nucleotides upstream of the start codon where initiating ribosomes have been stalled with these sequences in their P site. Further analysis in xrn4 mutant plants indicates that cotranslational RNA decay is XRN4 dependent. Additionally, studies in plants lacking CAP BINDING PROTEIN80/ABA HYPERSENSITIVE1, the largest subunit of the nuclear mRNA cap binding complex, reveal a role for this protein in cotranslational decay. In total, our results demonstrate the global prevalence and features of cotranslational RNA decay in a plant transcriptome.