Bioinformatic identification of novel putative photoreceptor specific cis-elements

Danko, Charles G.; McIlvain, Vera A.; Qin, Maochun; Knox, Barry E.; Pertsov, Arkady M.

doi:10.1186/1471-2105-8-407

Cited by 4 publications

(5 citation statements)

References 59 publications

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“…To address this possibility, we searched the MDM2 P1 and P2 promoters for cone-specific control elements that were identified in an unbiased bioinformatics analysis (Danko et al, 2007). This revealed an element in the human but not mouse P2 promoter that matched a cone-specific RXR-like element (Danko et al, 2007) at each of six invariant positions, and matched the consensus RXRγ homodimer binding site (Dowhan et al, 1994) at 14 of 15 positions (Figure 7A). We then examined whether this human-specific element promotes MDM2 expression, using an MDM2-P2-Luc reporter gene and a mutant ΔRXR version that had two human-to-mouse nucleotide substitutions.…”

Section: Resultsmentioning

confidence: 99%

“…(A) A human MDM2 P2 promoter element (second row) with identity to a cone-specific RXR element (Danko et al, 2007) at each of six invariant positions (top row, underlined), and identity to the consensus RXRγ homodimer binding site at 14 of 15 positions (third row, shaded, from Table 1 of Dowhan et al, 1994), but differing from murine sequences (fifth row, aligned as in Figure S13). Human-to-mouse substitutions in P2-Luc-ΔRXR (fourth row) are underlined.…”

Section: Figurementioning

confidence: 99%

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Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Fang

Lee

et al. 2009

Cell

211

286

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SUMMARY Retinoblastomas develop due to the loss of the Rb protein, yet the cell type in which Rb suppresses retinoblastoma, and the cellular circuitry that underlies the need for Rb are undefined. Here, we show that retinoblastoma cells express markers of post-mitotic cone precursors, but not markers of other retinal cell types. We also demonstrate that human cone precursors prominently express MDM2 and N-Myc, that retinoblastoma cells require both of these proteins for proliferation and survival, and that MDM2 is specifically needed to suppress ARF-induced apoptosis in cultured retinoblastoma cells. Interestingly, retinoblastoma cell MDM2 expression was regulated by the cone-specific RXRγ transcription factor and a human-specific RXRγ consensus binding site, and proliferation required RXRγ as well as the cone-specific thyroid hormone receptor-β2. These findings provide support for a cone precursor origin of retinoblastoma and suggest that human cone-specific signaling circuitry sensitizes to the oncogenic effects of RB1 mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Fang

Lee

et al. 2009

Cell

211

286

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“…We used two strategies to analyze the core promoter region of co-regulated genes. First, the motif discovery algorithm Iterative Alignment/Modular Motif Selection (IAMMS) [ 24 ] was used to identify putative regulatory sites de novo . Second, we searched for an enrichment of known regulatory motifs using the gene set enrichment analysis (GSEA) tools [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…The upstream region of genes in the contractile, energy generation, and protein translation sets were scanned against the background promoter set using IAMMS, as described previously [ 24 ]. In the initial stage, IAMMS detected 10,240, 19,665, and 16,719 motifs to test for enrichment in the contractile, energy, and translation promoter groups, respectively.…”

Section: Methodsmentioning

confidence: 99%

Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease

Danko

Pertsov

2009

BMC Med Genomics

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BackgroundCardiomyopathies, degenerative diseases of cardiac muscle, are among the leading causes of death in the developed world. Microarray studies of cardiomyopathies have identified up to several hundred genes that significantly alter their expression patterns as the disease progresses. However, the regulatory mechanisms driving these changes, in particular the networks of transcription factors involved, remain poorly understood. Our goals are (A) to identify modules of co-regulated genes that undergo similar changes in expression in various types of cardiomyopathies, and (B) to reveal the specific pattern of transcription factor binding sites, cis-elements, in the proximal promoter region of genes comprising such modules.MethodsWe analyzed 149 microarray samples from human hypertrophic and dilated cardiomyopathies of various etiologies. Hierarchical clustering and Gene Ontology annotations were applied to identify modules enriched in genes with highly correlated expression and a similar physiological function. To discover motifs that may underly changes in expression, we used the promoter regions for genes in three of the most interesting modules as input to motif discovery algorithms. The resulting motifs were used to construct a probabilistic model predictive of changes in expression across different cardiomyopathies.ResultsWe found that three modules with the highest degree of functional enrichment contain genes involved in myocardial contraction (n = 9), energy generation (n = 20), or protein translation (n = 20). Using motif discovery tools revealed that genes in the contractile module were found to contain a TATA-box followed by a CACC-box, and are depleted in other GC-rich motifs; whereas genes in the translation module contain a pyrimidine-rich initiator, Elk-1, SP-1, and a novel motif with a GCGC core. Using a naïve Bayes classifier revealed that patterns of motifs are statistically predictive of expression patterns, with odds ratios of 2.7 (contractile), 1.9 (energy generation), and 5.5 (protein translation).ConclusionWe identified patterns comprised of putative cis-regulatory motifs enriched in the upstream promoter sequence of genes that undergo similar changes in expression secondary to cardiomyopathies of various etiologies. Our analysis is a first step towards understanding transcription factor networks that are active in regulating gene expression during degenerative heart disease.

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“…The availability of these datasets has resulted in more efforts at generating a GRN for retinal development than for any other ocular component 148–154. The use of motif discovery algorithms has led to the prediction of several rod‐ and cone‐specific CREs and some of these have been experimentally validated 155. Specifically, promoters of cone‐expressed genes are found to contain an enrichment of predicted motifs for Rx and engrailed family members, whereas promoters of rod‐expressed genes are found to contain predicted interleukin 6 (IL‐6) effector motifs.…”

Section: Systems‐level Analyses Of Eye Developmentmentioning

confidence: 99%

Building the developmental oculome: systems biology in vertebrate eye development and disease

Lachke

Maas

2010

WIREs Mechanisms of Disease

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The vertebrate eye is a sophisticated multi-component organ that has been actively studied for over a century, resulting in the identification of the major embryonic and molecular events involved in its complex developmental program. Data gathered so far provides sufficient information to construct a rudimentary network of the various signaling molecules, transcription factors and their targets for several key stages of this process. With the advent of genomic technologies, there has been a rapid expansion in our ability to collect and process biological information, and the use of systems-level approaches to study specific aspects of vertebrate eye development has already commenced. This is beginning to result in the definition of the dynamic developmental networks that operate in ocular tissues, and the interactions of such networks between coordinately developing ocular tissues. Such an integrative understanding of the eye by a comprehensive systems-level analysis can be termed the “oculome”, and that of serial developmental stages of the eye as it transits from its initiation to a fully formed functional organ represents the “developmental oculome”. Construction of the developmental oculome will allow novel mechanistic insights that are essential for organ regeneration-based therapeutic applications, and the generation of computational models for eye disease states to predict the effects of drugs. This review discusses our present understanding of two of the individual components of the developing vertebrate eye – the lens and retina – at both the molecular and systems levels, and outlines the directions and tools required for construction of the developmental oculome.

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Bioinformatic identification of novel putative photoreceptor specific cis-elements

Cited by 4 publications

References 59 publications

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Retinoblastoma Has Properties of a Cone Precursor Tumor and Depends Upon Cone-Specific MDM2 Signaling

Identification of gene co-regulatory modules and associated cis-elements involved in degenerative heart disease

Building the developmental oculome: systems biology in vertebrate eye development and disease

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