Yu, Xiang
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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 RRNA 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.Publication Genome-Wide TOP2A DNA Cleavage is Biased Toward Translocated and Highly Transcribed Loci(2017-07-01) Yu, Xiang; Davenport, James W; Urtishak, Karen A; Carillo, Marie L; Rappaport, Eric F; Gosai, Sager J; Kolaris, Christos P; Gregory, Brian D; Byl, Jo Ann W; Felix, Carolyn A; Osheroff, NeilType II topoisomerases orchestrate proper DNA topology, and they are the targets of anti-cancer drugs that cause treatment-related leukemias with balanced translocations. Here, we develop a high-throughput sequencing technology to define TOP2 cleavage sites at single-base precision, and use the technology to characterize TOP2A cleavage genome-wide in the human K562 leukemia cell line. We find that TOP2A cleavage has functionally conserved local sequence preferences, occurs in cleavage cluster regions (CCRs), and is enriched in introns and lincRNA loci. TOP2A CCRs are biased toward the distal regions of gene bodies, and TOP2 poisons cause a proximal shift in their distribution. We find high TOP2A cleavage levels in genes involved in translocations in TOP2 poison–related leukemia. In addition, we find that a large proportion of genes involved in oncogenic translocations overall contain TOP2A CCRs. The TOP2A cleavage of coding and lincRNA genes is independently associated with both length and transcript abundance. Comparisons to ENCODE data reveal distinct TOP2A CCR clusters that overlap with marks of transcription, open chromatin, and enhancers. Our findings implicate TOP2A cleavage as a broad DNA damage mechanism in oncogenic translocations as well as a functional role of TOP2A cleavage in regulating transcription elongation and gene activation.Publication Chromatin Dynamics during the Differentiation of Long-Term Hematopoietic Stem Cells to Multipotent Progenitors(2017-06-01) Yu, Xiang; Bhavanasi, Dheeraj; Wu, Chao; Gregory, Brian D; Wang, Hong; Huang, JianHematopoietic stem cells (HSCs) are characterized by their self-renewal potential and ability to differentiate into multiple blood lineages.1,2 They are essential for lifelong blood production and represent 1 of the best-studied somatic stem cell systems.2-4 Several decades of successful bone marrow transplants have demonstrated the therapeutic importance of HSCs.5 Much progress has been made to understand the regulatory network of HSC self-renewal and differentiation.6,7 Several studies suggest that epigenetic mechanisms play an important role in controlling HSC renewal and lineage commitment.8-12 Understanding the regulatory mechanisms of HSC self-renewal and differentiation is important for both basic stem cell biology and improving the quality of stem cell transplantation in clinical settings.