OUP accepted manuscript

Tyner, Cath; Barber, Galt P.; Casper, Jonathan D.; Clawson, Hiram; Diekhans, Mark; Eisenhart, Christopher; Fischer, Clayton M.; Gibson, David J.; Gonzalez, Jairo Navarro; Guruvadoo, Luvina; Haeussler, Maximilian; Heitner, Steve; Hinrichs, Angie S.; Karolchik, Donna; Lee, Brian T.; Nejad, Parisa; Raney, Brian J.; Rosenbloom, Kate R.; Speir, Matthew L; Villarreal, Chris; Vivian, John; Zweig, Ann S.; Haussler, David; Kuhn, Robert M.; Kent, W. James

doi:10.1093/nar/gkw1134

Cited by 234 publications

(163 citation statements)

References 49 publications

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“…Data culled from chromatin immunoprecipitation sequencing (ChipSeq) experiments 20 demonstrated that the progesterone receptor binds directly to the PDK4 promoter as well as a region approximately 10kb upstream, and receptor binding was markedly increased by the presence of progesterone (Online Figure IVF). ENCODE data 21 demonstrates that both of these regions are hypersensitive to DNAseI digestion, and contain a high amount of histone acetylation at H3K27, indicating high transcriptional regulatory activity at both sites. Both regulatory sites contain strong candidate progesterone-binding sequences 22 (Online Figure IVF), consistent with the observed progesterone receptor binding.…”

Section: Resultsmentioning

confidence: 99%

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Liu

Rowe

Yang

et al. 2017

Circulation Research

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Rationale Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results We use here 13C-glucose, 13C-lactate, and 13C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Conclusions Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling.

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Section: Resultsmentioning

confidence: 99%

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Liu

Rowe

Yang

et al. 2017

Circulation Research

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“…Significance of predicted folding stability was assessed by shuffling the original sequence 10,000 times while preserving dinucleotide frequency (Jiang et al, 2008), computing the fold and Δ G for each shuffled sequence, and then designating the empirical P value as the fraction of shuffled sequences with the same or lower predicted Δ G . Covariations in the CENPB 3′-end structure were detected by RNAalifold (Lorenz et al, 2011), using a multiple sequence alignment of 62 mammalian species downloaded from UCSC Table browser (Tyner et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

Widespread Influence of 3′-End Structures on Mammalian mRNA Processing and Stability

Bartel

2017

Cell

128

115

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SUMMARY The physiological relevance of structures within mammalian mRNAs has been elusive, as these mRNAs are less folded in cells than in vitro and have predicted secondary structures no more stable than those of random sequences. Here, we investigate possibility that mRNA structures facilitate the 3′-end processing of thousands of human mRNAs by juxtaposing poly(A) signals (PASs) and cleavage sites that are otherwise too far apart. We find that RNA structures are predicted to be more prevalent within these extended 3′-end regions than within PAS-upstream regions, and indeed are substantially more folded within cells, as determined by intracellular probing. Analyses of thousands of ectopically expressed variants demonstrate that this folding both enhances processing and increases mRNA metabolic stability. Even folds with predicted stabilities resembling those of random sequences can enhance processing. Structure-controlled processing can also regulate neighboring gene expression. Thus, RNA structure has widespread roles in mammalian mRNA biogenesis and metabolism.

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“…Somatic Mutation Datasets and Protein–Protein Interaction Datasets : Six nonsilent somatic mutation (nonsense mutations, missense mutations, frame‐shift indels, splice site mutations, or stop codon read‐throughs) datasets of Pan‐Cancer (namely, AWG, bcgsc, bcm, broad, ucsc, and wustl) and 19 datasets of individual cancer types were collected from the TCGA database by UCSC Browser42 (https://xenabrowser.net/datapages/) (Tables S1 and S2, Supporting Information). Two independently developed PPI datasets HumanNet24 and STRINGv1025 were downloaded from their respective websites.…”

Section: Methodsmentioning

confidence: 99%

MaxMIF: A New Method for Identifying Cancer Driver Genes through Effective Data Integration

Hou

Gao

et al. 2018

Advanced Science

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Identification of a few cancer driver mutation genes from a much larger number of passenger mutation genes in cancer samples remains a highly challenging task. Here, a novel method for distinguishing the driver genes from the passenger genes by effective integration of somatic mutation data and molecular interaction data using a maximal mutational impact function (MaxMIF) is presented. When evaluated on six somatic mutation datasets of Pan‐Cancer and 19 datasets of different cancer types from TCGA, MaxMIF almost always significantly outperforms all the existing state‐of‐the‐art methods in terms of predictive accuracy, sensitivity, and specificity. It recovers about 30% more known cancer genes in 500 top‐ranked candidate genes than the best among the other tools evaluated. MaxMIF is also highly robust to data perturbation. Intriguingly, MaxMIF is able to identify potential cancer driver genes, with strong experimental data support. Therefore, MaxMIF can be very useful for identifying or prioritizing cancer driver genes in the increasing number of available cancer genomic data.

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OUP accepted manuscript

Cited by 234 publications

References 49 publications

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy

Widespread Influence of 3′-End Structures on Mammalian mRNA Processing and Stability

MaxMIF: A New Method for Identifying Cancer Driver Genes through Effective Data Integration

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