Cyber-T web server: differential analysis of high-throughput data

Kayala, Matthew A.; Baldi, Pierre

doi:10.1093/nar/gks420

Cited by 140 publications

(131 citation statements)

References 27 publications

(35 reference statements)

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“…For each of the four ZT time points, a regularized paired T-test was performed to compare the mean intensity between Clock −/− and WT liver samples using CyberT (64,65). The sliding window size for Bayesian SD estimation was set to 7.…”

Section: Methodsmentioning

confidence: 99%

Circadian acetylome reveals regulation of mitochondrial metabolic pathways

Masri¹,

Patel

Eckel‐Mahan³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

112

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The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock −/− ) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock −/− mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.chromatin | epigenetics T he circadian clock is a hierarchical network of biological pacemakers found in all tissues that direct and maintain proper rhythms in endocrine and metabolic pathways required for organism homeostasis (1, 2). The clock machinery consists of core transcription factors, which drive expression of clock-controlled genes (CCGs). An estimated 10% or more of the genome is believed to oscillate in a circadian and clock-controlled manner (3-5). The clock machinery is tightly regulated by transcriptional/translational events (6); posttranslational modifications of key circadian proteins (7), including phosphorylation (8-11), acetylation (12-15), SUMOylation (16) and ubiquitylation (17-19); as well as enzymatic feedback loops that directly link metabolites such as NAD + with enzymes involved in circadian function and ultimately regulation of CCG expression (20,21). Importantly, reversible lysine acetylation of clock proteins involved in clock control has been shown for aryl hydrocarbon receptor nuclear translocator-like (BMAL1) (13), Period 2 (PER2) (12), and the glucocorticoid receptor (GR) (14). Furthermore, subsequent reversible deacetylation of BMAL1 (15) and PER2 (12) by the NAD + -dependent histone deacetylase sirtuin 1 appear to be critical events for maintaining proper biological circadian rhythmicity.Our current understanding of reversible lysine acetylation extends to both histone and nonhistone proteins. Protein acetylation has been implicated in regulating gene expression programs (22-24), cellular structural integrity maintenance (25, 26), metabolic/energy control (27, 28), and cellular growth/proliferation pathways (29). Furthermore, histone acetyltransferases as well as histone deacetylases target specific lysine residues, and the specific addition or re...

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Section: Methodsmentioning

confidence: 99%

Circadian acetylome reveals regulation of mitochondrial metabolic pathways

Masri¹,

Patel

Eckel‐Mahan³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

135

112

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“…In total, 16,993 probe sets were deemed present by the MAS5.0 algorithm. Once processed, Guanosine-Cytosine Robust Multiarray Average-normalized gene expression values were analyzed to identify differentially expressed genes by a regularized Student's t test based on a Bayesian statistical framework using the software program Cyber-T (Kayala and Baldi, 2012). Changes were considered significant at a false discovery rate correction level of PPDE(,P ) .…”

Section: Microarray Analysismentioning

confidence: 99%

AtWRKY40 and AtWRKY63 Modulate the Expression of Stress-Responsive Nuclear Genes Encoding Mitochondrial and Chloroplast Proteins

et al. 2013

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The expression of a variety of nuclear genes encoding mitochondrial proteins is known to adapt to changes in environmental conditions and retrograde signaling. The presence of putative WRKY transcription factor binding sites (W-boxes) in the promoters of many of these genes prompted a screen of 72 annotated WRKY factors in the Arabidopsis (Arabidopsis thaliana) genome for regulators of transcripts encoding mitochondrial proteins. A large-scale yeast one-hybrid screen was used to identify WRKY factors that bind the promoters of marker genes (Alternative oxidase1a, NADH dehydrogenaseB2, and the AAA ATPase Ubiquinol-cytochrome c reductase synthesis1), and interactions were confirmed using electromobility shift assays. Transgenic overexpression and knockout lines for 12 binding WRKY factors were generated and tested for altered expression of the marker genes during normal and stress conditions. AtWRKY40 was found to be a repressor of antimycin A-induced mitochondrial retrograde expression and high-light-induced signaling, while AtWRKY63 was identified as an activator. Genome-wide expression analysis following high-light stress in transgenic lines with perturbed AtWRKY40 and AtWRKY63 function revealed that these factors are involved in regulating stress-responsive genes encoding mitochondrial and chloroplast proteins but have little effect on more constitutively expressed genes encoding organellar proteins. Furthermore, it appears that AtWRKY40 and AtWRKY63 are particularly involved in regulating the expression of genes responding commonly to both mitochondrial and chloroplast dysfunction but not of genes responding to either mitochondrial or chloroplast perturbation. In conclusion, this study establishes the role of WRKY transcription factors in the coordination of stress-responsive genes encoding mitochondrial and chloroplast proteins.

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“…Percellome microarray data were analyzed using CyberT (Kayala and Baldi, 2012). We did not use low value thresholding/offsetting or log/VSN normalizations.…”

Section: Percellome Microarray Analysismentioning

confidence: 99%

Active repression by RARγ signaling is required for vertebrate axial elongation

et al. 2014

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Retinoic acid receptor gamma 2 (RARγ2) is the major RAR isoform expressed throughout the caudal axial progenitor domain in vertebrates. During a microarray screen to identify RAR targets, we identified a subset of genes that pattern caudal structures or promote axial elongation and are upregulated by increased RARmediated repression. Previous studies have suggested that RAR is present in the caudal domain, but is quiescent until its activation in late stage embryos terminates axial elongation. By contrast, we show here that RARγ2 is engaged in all stages of axial elongation, not solely as a terminator of axial growth. In the absence of RA, RARγ2 represses transcriptional activity in vivo and maintains the pool of caudal progenitor cells and presomitic mesoderm. In the presence of RA, RARγ2 serves as an activator, facilitating somite differentiation. Treatment with an RARγ-selective inverse agonist (NRX205099) or overexpression of dominant-negative RARγ increases the expression of posterior Hox genes and that of marker genes for presomitic mesoderm and the chordoneural hinge. Conversely, when RAR-mediated repression is reduced by overexpressing a dominant-negative co-repressor (c-SMRT), a constitutively active RAR (VP16-RARγ2), or by treatment with an RARγ-selective agonist (NRX204647), expression of caudal genes is diminished and extension of the body axis is prematurely terminated. Hence, gene repression mediated by the unliganded RARγ2-co-repressor complex constitutes a novel mechanism to regulate and facilitate the correct expression levels and spatial restriction of key genes that maintain the caudal progenitor pool during axial elongation in Xenopus embryos.

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Cyber-T web server: differential analysis of high-throughput data

Cited by 140 publications

References 27 publications

Circadian acetylome reveals regulation of mitochondrial metabolic pathways

Circadian acetylome reveals regulation of mitochondrial metabolic pathways

AtWRKY40 and AtWRKY63 Modulate the Expression of Stress-Responsive Nuclear Genes Encoding Mitochondrial and Chloroplast Proteins

Active repression by RARγ signaling is required for vertebrate axial elongation

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