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SIGMA2: A system for the integrative genomic multi-dimensional analysis of cancer genomes, epigenomes, and transcriptomes
Raj Chari, Bradley P Coe, Craig Wedseltoft, Marie Benetti, Ian M Wilson, Emily A Vucic, Calum MacAulay, Raymond T Ng, Wan L Lam
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-422
Abstract: Here, we present SIGMA2, a system for the integrative genomic multi-dimensional analysis of cancer genomes, epigenomes, and transcriptomes. Multi-dimensional datasets can be simultaneously visualized and analyzed with respect to each dimension, allowing combinatorial integration of the different assays belonging to the different 'omics.The identification of genes altered at multiple levels such as copy number, loss of heterozygosity (LOH), DNA methylation and the detection of consequential changes in gene expression can be concertedly performed, establishing SIGMA2 as a novel tool to facilitate the high throughput systems biology analysis of cancer.Multiple mechanisms of gene disruption have been shown to be important in the development of cancer. Genetic alterations (mutations, changes in gene dosage, allele imbalance) and epigenetic alterations (changes in DNA methylation and histone modification states) are responsible for changing the expression of genes. High throughput approaches have afforded the ability to interrogate the genomic, epigenomic and gene expression (transcriptomic) profiles at unprecedented resolution [1-6]. However, a gene can be disrupted by one or by a combination of mechanisms, therefore, investigation in a single 'omics dimension (genomics, epigenomics, or transcriptomics) alone cannot detect all disrupted genes in a given tumor. Moreover, individual tumors may have different patterns of gene disruption, by different mechanisms for a given gene while achieving the same net effect on phenotype. Hence, a multi-dimensional approach is required to identify the causal events at the DNA level and understand their downstream consequences.The current state of software for global profile comparison typically focuses on analyzing and displaying data from a single dimension, for example CGH Fusion (infoQuant Ltd, London, UK) for DNA copy number profile analysis and GeneSpring (Agilent Technologies, Santa Clara, CA, USA) for gene expression profile ana
Microdissection of Shoot Meristem Functional Domains  [PDF]
Lionel Brooks III equal contributor,Josh Strable equal contributor,Xiaolan Zhang,Kazuhiro Ohtsu,Ruilian Zhou,Ananda Sarkar,Sarah Hargreaves,Robert J. Elshire,Douglas Eudy,Teresa Pawlowska,Doreen Ware,Diane Janick-Buckner,Brent Buckner,Marja C. P. Timmermans,Patrick S. Schnable,Dan Nettleton,Michael J. Scanlon
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000476
Abstract: The shoot apical meristem (SAM) maintains a pool of indeterminate cells within the SAM proper, while lateral organs are initiated from the SAM periphery. Laser microdissection–microarray technology was used to compare transcriptional profiles within these SAM domains to identify novel maize genes that function during leaf development. Nine hundred and sixty-two differentially expressed maize genes were detected; control genes known to be upregulated in the initiating leaf (P0/P1) or in the SAM proper verified the precision of the microdissections. Genes involved in cell division/growth, cell wall biosynthesis, chromatin remodeling, RNA binding, and translation are especially upregulated in initiating leaves, whereas genes functioning during protein fate and DNA repair are more abundant in the SAM proper. In situ hybridization analyses confirmed the expression patterns of six previously uncharacterized maize genes upregulated in the P0/P1. P0/P1-upregulated genes that were also shown to be downregulated in leaf-arrested shoots treated with an auxin transport inhibitor are especially implicated to function during early events in maize leaf initiation. Reverse genetic analyses of asceapen1 (asc1), a maize D4-cyclin gene upregulated in the P0/P1, revealed novel leaf phenotypes, less genetic redundancy, and expanded D4-CYCLIN function during maize shoot development as compared to Arabidopsis. These analyses generated a unique SAM domain-specific database that provides new insight into SAM function and a useful platform for reverse genetic analyses of shoot development in maize.
Epigenomes under scrutiny
Jacqueline E Mermoud
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-5-308
Abstract: Uncovering the foundations of the self-renewing capacity of stem cells and their ability to give rise to multiple cell types holds tremendous promise for understanding the basic principles of eukaryotic development, cell differentiation and genome reprogramming. Epigenetic mechanisms that affect chromatin organization play a fundamental role in these processes by controlling accessibility of the genome at the right time and right place. A recent stem-cell meeting in London provided a welcome opportunity to hear the latest advances on the fundamental determinants of stem-cell fates with an emphasis on epigenetic regulation in the mouse. The highlights selected here focus on the extent to which epigenetic mechanisms impact on stem-cell and developmental biology and on the underlying molecular machinery.One challenge is the quest for chromatin signatures indicative of the developmental potential of a cell. This major task is being tackled by large-scale profiling of epigenetic modifications within the genomes of stem-cell populations that have broad developmental plasticity and the lineage-committed cells derived from them. Alexander Meissner (Harvard University, Boston, USA) presented a compelling technological advance enabling the analysis and comparison of global DNA methylation patterns in a high-throughput manner and, what is more, at nucleotide resolution. The power of this approach comes from bisulfite treatment of DNA, which converts all unmethylated cytosines to uracil, coupled with Solexa next-generation DNA sequencing technology. DNA fragments from, for example, restriction digests, are selected by size, generating a 'reduced representation' of the genome of a cell type or tissue. Libraries of bisulfite-converted DNA fragments can be compared to the same fraction of the genome across different samples, such as preparations from distinct developmental stages. Meissner and colleagues examined the dynamics of DNA methylation as mouse embryonic stem cells (ES ce
Human Sclera Maintains Common Characteristics with Cartilage throughout Evolution  [PDF]
Yuko Seko, Noriyuki Azuma, Yoriko Takahashi, Hatsune Makino, Toshiyuki Morito, Takeshi Muneta, Kenji Matsumoto, Hirohisa Saito, Ichiro Sekiya, Akihiro Umezawa
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003709
Abstract: Background The sclera maintains and protects the eye ball, which receives visual inputs. Although the sclera does not contribute significantly to visual perception, scleral diseases such as refractory scleritis, scleral perforation and pathological myopia are considered incurable or difficult to cure. The aim of this study is to identify characteristics of the human sclera as one of the connective tissues derived from the neural crest and mesoderm. Methodology/Principal Findings We have demonstrated microarray data of cultured human infant scleral cells. Hierarchical clustering was performed to group scleral cells and other mesenchymal cells into subcategories. Hierarchical clustering analysis showed similarity between scleral cells and auricular cartilage-derived cells. Cultured micromasses of scleral cells exposed to TGF-βs and BMP2 produced an abundant matrix. The expression of cartilage-associated genes, such as Indian hedge hog, type X collagen, and MMP13, was up-regulated within 3 weeks in vitro. These results suggest that human ‘sclera’-derived cells can be considered chondrocytes when cultured ex vivo. Conclusions/Significance Our present study shows a chondrogenic potential of human sclera. Interestingly, the sclera of certain vertebrates, such as birds and fish, is composed of hyaline cartilage. Although the human sclera is not a cartilaginous tissue, the human sclera maintains chondrogenic potential throughout evolution. In addition, our findings directly explain an enigma that the sclera and the joint cartilage are common targets of inflammatory cells in rheumatic arthritis. The present global gene expression database will contribute to the clarification of the pathogenesis of developmental diseases such as high myopia.
The Human Brain Maintains Contradictory and Redundant Auditory Sensory Predictions  [PDF]
Marika Pieszek, Andreas Widmann, Thomas Gruber, Erich Schr?ger
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053634
Abstract: Computational and experimental research has revealed that auditory sensory predictions are derived from regularities of the current environment by using internal generative models. However, so far, what has not been addressed is how the auditory system handles situations giving rise to redundant or even contradictory predictions derived from different sources of information. To this end, we measured error signals in the event-related brain potentials (ERPs) in response to violations of auditory predictions. Sounds could be predicted on the basis of overall probability, i.e., one sound was presented frequently and another sound rarely. Furthermore, each sound was predicted by an informative visual cue. Participants’ task was to use the cue and to discriminate the two sounds as fast as possible. Violations of the probability based prediction (i.e., a rare sound) as well as violations of the visual-auditory prediction (i.e., an incongruent sound) elicited error signals in the ERPs (Mismatch Negativity [MMN] and Incongruency Response [IR]). Particular error signals were observed even in case the overall probability and the visual symbol predicted different sounds. That is, the auditory system concurrently maintains and tests contradictory predictions. Moreover, if the same sound was predicted, we observed an additive error signal (scalp potential and primary current density) equaling the sum of the specific error signals. Thus, the auditory system maintains and tolerates functionally independently represented redundant and contradictory predictions. We argue that the auditory system exploits all currently active regularities in order to optimally prepare for future events.
Plant Epigenetics: From genomes to epigenomes
Alain RIVAL,Thierry BEULé,Frédérique ABERLENC BERTOSSI,James TREGEAR
Notulae Botanicae Horti Agrobotanici Cluj-Napoca , 2010,
Abstract: Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. In recent years, this field has attracted increasing attention as more epigenetic mechanisms affecting gene activity are being discovered. Such processes involve a complex interplay between DNA methylation, histone modifications, and non-coding RNAs, notably small interfering RNAs (siRNAs) and micro RNAs (miRNAs). Epigenetic regulation is not only important for generating differentiated cell types during plant development, but also in maintaining the stability and integrity of their respective gene expression profiles. Although epigenetic processes are essential for normal development, they can become misdirected which leads to abnormal phenotypes and diseases, especially cancer. Sensing environmental changes and initiating a quick, reversible and appropriate response in terms of modified gene expression is of paramount importance for plants which are sessile autotrophs. Although epigenetic mechanisms help to protect plant cells from the activity of parasitic sequences such as transposable elements, this defense can complicate the genetic engineering process through transcriptional gene silencing. Epigenetic phenomena have economic relevance in the case of somaclonal variation: a genetic and phenotypic variation among clonally propagated plants from a single donor genotype. The success of sequencing projects on model plants has created widespread interest in exploring the epigenome in order to elucidate how plant cell decipher and execute the information stored and encoded in the genome. New high-throughput techniques are making it easier to map DNA methylation patterns on a large scale and results have already provided surprises.
PKMζ Maintains Spatial, Instrumental, and Classically Conditioned Long-Term Memories  [PDF]
Peter Serrano,Eugenia L. Friedman,Jana Kenney,Stephen M. Taubenfeld,Joshua M. Zimmerman,John Hanna,Cristina Alberini,Ann E. Kelley,Stephen Maren,Jerry W. Rudy,Jerry C. P. Yin,Todd C. Sacktor,André A. Fenton
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0060318
Abstract: How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMζ activity. We then examined, using ZIP, the effect of PKMζ inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMζ inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ inhibition in the BLA impaired retention of classical conditioned stimulus–unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.
PKMζ Maintains Spatial, Instrumental, and Classically Conditioned Long-Term Memories  [PDF]
Peter Serrano equal contributor,Eugenia L Friedman equal contributor,Jana Kenney,Stephen M Taubenfeld,Joshua M Zimmerman,John Hanna,Cristina Alberini,Ann E Kelley ?,Stephen Maren,Jerry W Rudy,Jerry C. P Yin,Todd C Sacktor ,André A Fenton
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.0060318
Abstract: How long-term memories are stored is a fundamental question in neuroscience. The first molecular mechanism for long-term memory storage in the brain was recently identified as the persistent action of protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C (PKC) isoform critical for the maintenance of long-term potentiation (LTP). PKMζ maintains aversively conditioned associations, but what general form of information the kinase encodes in the brain is unknown. We first confirmed the specificity of the action of zeta inhibitory peptide (ZIP) by disrupting long-term memory for active place avoidance with chelerythrine, a second inhibitor of PKMζ activity. We then examined, using ZIP, the effect of PKMζ inhibition in dorsal hippocampus (DH) and basolateral amygdala (BLA) on retention of 1-d-old information acquired in the radial arm maze, water maze, inhibitory avoidance, and contextual and cued fear conditioning paradigms. In the DH, PKMζ inhibition selectively disrupted retention of information for spatial reference, but not spatial working memory in the radial arm maze, and precise, but not coarse spatial information in the water maze. Thus retention of accurate spatial, but not procedural and contextual information required PKMζ activity. Similarly, PKMζ inhibition in the hippocampus did not affect contextual information after fear conditioning. In contrast, PKMζ inhibition in the BLA impaired retention of classical conditioned stimulus–unconditioned stimulus (CS-US) associations for both contextual and auditory fear, as well as instrumentally conditioned inhibitory avoidance. PKMζ inhibition had no effect on postshock freezing, indicating fear expression mediated by the BLA remained intact. Thus, persistent PKMζ activity is a general mechanism for both appetitively and aversively motivated retention of specific, accurate learned information, but is not required for processing contextual, imprecise, or procedural information.
Cooperative Interaction between Phosphorylation Sites on PERIOD Maintains Circadian Period in Drosophila  [PDF]
David S. Garbe,Yanshan Fang,Xiangzhong Zheng,Mallory Sowcik,Rana Anjum,Steven P. Gygi,Amita Sehgal
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003749
Abstract: Circadian rhythms in Drosophila rely on cyclic regulation of the period (per) and timeless (tim) clock genes. The molecular cycle requires rhythmic phosphorylation of PER and TIM proteins, which is mediated by several kinases and phosphatases such as Protein Phosphatase-2A (PP2A) and Protein Phosphatase-1 (PP1). Here, we used mass spectrometry to identify 35 “phospho-occupied” serine/threonine residues within PER, 24 of which are specifically regulated by PP1/PP2A. We found that cell culture assays were not good predictors of protein function in flies and so we generated per transgenes carrying phosphorylation site mutations and tested for rescue of the per01 arrhythmic phenotype. Surprisingly, most transgenes restore wild type rhythms despite carrying mutations in several phosphorylation sites. One particular transgene, in which T610 and S613 are mutated to alanine, restores daily rhythmicity, but dramatically lengthens the period to ~30 hrs. Interestingly, the single S613A mutation extends the period by 2–3 hours, while the single T610A mutation has a minimal effect, suggesting these phospho-residues cooperate to control period length. Conservation of S613 from flies to humans suggests that it possesses a critical clock function, and mutational analysis of residues surrounding T610/S613 implicates the entire region in determining circadian period. Biochemical and immunohistochemical data indicate defects in overall phosphorylation and altered timely degradation of PER carrying the double or single S613A mutation(s). The PER-T610A/S613A mutant also alters CLK phosphorylation and CLK-mediated output. Lastly, we show that a mutation at a previously identified site, S596, is largely epistatic to S613A, suggesting that S613 negatively regulates phosphorylation at S596. Together these data establish functional significance for a new domain of PER, demonstrate that cooperativity between phosphorylation sites maintains PER function, and support a model in which specific phosphorylated regions regulate others to control circadian period.
Genome scale transcriptome analysis of shoot organogenesis in Populus
Yanghuan Bao, Palitha Dharmawardhana, Todd C Mockler, Steven H Strauss
BMC Plant Biology , 2009, DOI: 10.1186/1471-2229-9-132
Abstract: We analyzed gene expression during poplar in vitro dedifferentiation and shoot regeneration using an Affymetrix array representing over 56,000 poplar transcripts. We focused on callus induction and shoot formation, thus we sampled RNAs from tissues: prior to callus induction, 3 days and 15 days after callus induction, and 3 days and 8 days after the start of shoot induction. We used a female hybrid white poplar clone (INRA 717-1 B4, Populus tremula × P. alba) that is used widely as a model transgenic genotype. Approximately 15% of the monitored genes were significantly up-or down-regulated when controlling the false discovery rate (FDR) at 0.01; over 3,000 genes had a 5-fold or greater change in expression. We found a large initial change in expression after the beginning of hormone treatment (at the earliest stage of callus induction), and then a much smaller number of additional differentially expressed genes at subsequent regeneration stages. A total of 588 transcription factors that were distributed in 45 gene families were differentially regulated. Genes that showed strong differential expression included components of auxin and cytokinin signaling, selected cell division genes, and genes related to plastid development and photosynthesis. When compared with data on in vitro callogenesis in Arabidopsis, 25% (1,260) of up-regulated and 22% (748) of down-regulated genes were in common with the genes regulated in poplar during callus induction.The major regulatory events during plant cell organogenesis occur at early stages of dedifferentiation. The regulatory circuits reflect the combinational effects of transcriptional control and hormone signaling, and associated changes in light environment imposed during dedifferentiation.In vitro regeneration is a common research tool and important method for plant propagation. It is also essential for most forms of genetic transformation, which require the regeneration of single transgenic cells into non-chimeric organisms [
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