EBSeq-HMM: a Bayesian approach for identifying gene-expression changes in ordered RNA-seq experiments

Leng, Ning; Li, Yuan; McIntosh, Brian E.; Nguyen, Bao Kim; Duffin, Bret; Tian, Shulan; Thomson, James A.; Dewey, Colin N.; Stewart, Ron; Kendziorski, Christina

doi:10.1093/bioinformatics/btv193

Cited by 95 publications

(103 citation statements)

References 33 publications

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“…We used ebseq‐hmm software (Leng et al., 2015) to compute statistically significant time patterns. To reduce the complexity, the 4M and 10M samples were not included in this analysis.…”

Section: Resultsmentioning

confidence: 99%

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Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

et al. 2018

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SummaryAnimals show a large variability of lifespan, ranging from short‐lived as Caenorhabditis elegans to immortal as Hydra. A fascinating case is flatworms, in which reversal of aging by regeneration is proposed, yet conclusive evidence for this rejuvenation‐by‐regeneration hypothesis is lacking. We tested this hypothesis by inducing regeneration in the sexual free‐living flatworm Macrostomum lignano. We studied survival, fertility, morphology, and gene expression as a function of age. Here, we report that after regeneration, genes expressed in the germline are upregulated at all ages, but no signs of rejuvenation are observed. Instead, the animal appears to be substantially longer lived than previously appreciated, and genes expressed in stem cells are upregulated with age, while germline genes are downregulated. Remarkably, several genes with known beneficial effects on lifespan when overexpressed in mice and C. elegans are naturally upregulated with age in M. lignano, suggesting that molecular mechanism for offsetting negative consequences of aging has evolved in this animal. We therefore propose that M. lignano represents a novel powerful model for molecular studies of aging attenuation, and the identified aging gene expression patterns provide a valuable resource for further exploration of anti‐aging strategies.

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“…We used ebseq‐hmm software (Leng et al., 2015) to compute statistically significant time patterns. To reduce the complexity, the 4M and 10M samples were not included in this analysis.…”

Section: Resultsmentioning

confidence: 99%

“…EdgeR package and EBSeq‐HMM (Leng et al., 2015) were used to perform differential gene expression analysis.…”

Section: Methodsmentioning

confidence: 99%

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

et al. 2018

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“…The expression of each transcript was calculated using rsem-calculate-expression using the option -forwardprob 0. Differential expression was determined using EBSeq (v1.6) with the "MedianNorm" normalization method (26,27).…”

Section: Table 1 Primers Used For Qpcrmentioning

confidence: 99%

Identification and Characterization of the Physiological Gene Targets of the Essential Lytic Replicative Epstein-Barr Virus SM Protein

Thompson

Verma

et al. 2016

J Virol

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Epstein-Barr virus (EBV) SM protein is an essential lytic cycle protein with multiple posttranscriptional mechanisms of action. SM binds RNA and increases accumulation of specific EBV transcripts. Previous studies using microarrays and PCR have shown that SM-null mutants fail to accumulate several lytic cycle mRNAs and proteins at wild-type levels. However, the complete effect of SM on the EBV transcriptome has been incompletely characterized. Here we precisely identify the effects of SM on all EBV transcripts by high-throughput RNA sequencing, quantitative PCR (qPCR), and Northern blotting. The effect of SM on EBV mRNAs was highly skewed and was most evident on 13 late genes, demonstrating why SM is essential for infectious EBV production. EBV DNA replication was also partially impaired in SM mutants, suggesting additional roles for SM in EBV DNA replication. While it has been suggested that SM specificity is based on recognition of either RNA sequence motifs or other sequence properties, no such unifying property of SM-responsive targets was discernible. The binding affinity of mRNAs for SM also did not correlate with SM responsiveness. These data suggest that while target RNA binding by SM may be required for its effect, specific activation by SM is due to differences in inherent properties of individual transcripts. We therefore propose a new model for the mechanism of action and specificity of SM and its homologs in other herpesviruses: that they bind many RNAs but only enhance accumulation of those that are intrinsically unstable and poorly expressed. IMPORTANCEThis study examines the mechanism of action of EBV SM protein, which is essential for EBV replication and infectious virus production. Since SM protein is not similar to any cellular protein and has homologs in all other human herpesviruses, it has potential importance as a therapeutic target. Here we establish which EBV RNAs are most highly upregulated by SM, allowing us to understand why it is essential for EBV replication. By comparing and characterizing these RNA transcripts, we conclude that the mechanism of specific activity is unlikely to be based simply on preferential recognition of a target motif. Rather, SM binding to its target RNA may be necessary but not sufficient for enhancing accumulation of the RNA. Preferential effects of SM on its most responsive RNA targets may depend on other inherent characteristics of these specific mRNAs that require SM for efficient expression, such as RNA stability. E pstein-Barr virus (EBV) SM protein is an essential regulatory protein expressed by EBV during the lytic phase of replication (for reviews, see references 1 and 2). SM protein is detectable after immediate early gene expression and prior to expression of other early gene products (3, 4). When the SM gene is insertionally inactivated in recombinant EBV genomes, the resultant virus is incapable of completing the lytic cycle and producing infectious virions (5, 6). The exact reasons that SM is essential for lytic replication and virus pro...

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“…68 Differentially expressed (DE) genes and isoforms were identified using EBSeq. 69 Bowtie, RSEM and EBSeq (ver 1.3.2) 69 were ran using default parameters. Quality control on sequences was performed by FASTQC.…”

Section: Plasmid Transfection and Viral Transductionmentioning

confidence: 99%

Histone chaperone ASF1B promotes humanβ-cell proliferation via recruitment of histone H3.3

et al. 2016

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Anti-silencing function 1 (ASF1) is a histone H3-H4 chaperone involved in DNA replication and repair, and transcriptional regulation. Here, we identify ASF1B, the mammalian paralog to ASF1, as a proliferationinducing histone chaperone in human b-cells. Overexpression of ASF1B led to distinct transcriptional signatures consistent with increased cellular proliferation and reduced cellular death. Using multiple methods of monitoring proliferation and mitotic progression, we show that overexpression of ASF1B is sufficient to induce human b-cell proliferation. Co-expression of histone H3.3 further augmented b-cell proliferation, whereas suppression of endogenous H3.3 attenuated the stimulatory effect of ASF1B. Using the histone binding-deficient mutant of ASF1B (V94R), we show that histone binding to ASF1B is required for the induction of b-cell proliferation. In contrast to H3.3, overexpression of histone H3 variants H3.1 and H3.2 did not have an impact on ASF1B-mediated induction of proliferation. Our findings reveal a novel role of ASF1B in human b-cell replication and show that ASF1B and histone H3.3A synergistically stimulate human b-cell proliferation.

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EBSeq-HMM: a Bayesian approach for identifying gene-expression changes in ordered RNA-seq experiments

Cited by 95 publications

References 33 publications

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

Resilience to aging in the regeneration‐capable flatworm Macrostomum lignano

Identification and Characterization of the Physiological Gene Targets of the Essential Lytic Replicative Epstein-Barr Virus SM Protein

Histone chaperone ASF1B promotes humanβ-cell proliferation via recruitment of histone H3.3

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