Asap: A Framework for Over-Representation Statistics for Transcription Factor Binding Sites

Marstrand, Troels; Frellsen, Jes; Moltke, Ida; Thiim, Martin; Valen, Eivind; Retelska, Dorota; Krogh, Anders

doi:10.1371/journal.pone.0001623

Cited by 35 publications

(43 citation statements)

References 25 publications

(27 reference statements)

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“…We searched all sequence sets with all position weight matrices in the JASPAR CORE database, using the ASAP tool (27) with the following settings: pseudocounts equal to the square root of the position specific counts and 0 th order uniform background model. We used a score threshold corresponding to 75% of the scoring range for each specific matrix model (24).…”

Section: Computational Motif Analysismentioning

confidence: 99%

The genome landscape of ERα- and ERβ-binding DNA regions

Liu

Gao

Marstrand

et al. 2008

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

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In this article, we have applied the ChIP-on-chip approach to pursue a large scale identification of ER␣-and ER␤-binding DNA regions in intact chromatin. We show that there is a high degree of overlap between the regions identified as bound by ER␣ and ER␤, respectively, but there are also regions that are bound by ER␣ only in the presence of ER␤, as well as regions that are selectively bound by either receptor. Analysis of bound regions shows that regions bound by ER␣ have distinct properties in terms of genome landscape, sequence features, and conservation compared with regions that are bound by ER␤. ER␤-bound regions are, as a group, located more closely to transcription start sites. ER␣-and ER␤-bound regions differ in sequence properties, with ER␣-bound regions having an overrepresentation of TA-rich motifs including forkhead binding sites and ER␤-bound regions having a predominance of classical estrogen response elements (EREs) and GC-rich motifs. Differences in the properties of ER bound regions might explain some of the differences in gene expression programs and physiological effects shown by the respective estrogen receptors.bioinformatics ͉ estrogen response elements ͉ estrogen signaling ͉ gene expression ͉ nuclear receptors

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Section: Computational Motif Analysismentioning

confidence: 99%

The genome landscape of ERα- and ERβ-binding DNA regions

Liu

Gao

Marstrand

et al. 2008

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

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“…With a known role in post-transcriptional regulation of inflammation-related genes 16 HuR is a good candidate, so we scanned the list of genes deregulated following miR-9 inhibition for the presence of the consensus HuR-binding motif. 23 Intriguingly, using the Asap software package, 24 we found a highly significant overrepresentation of the HuR-binding motif among the deregulated transcripts compared to a group of between three independent experiments. (a, b) Biotinylated miR-9 or miR-34a were transfected into L428 cells and their ability to pull-down HuR (a) or DICER1 (b) mRNAs were assessed using qPCR.…”

Section: Introductionmentioning

confidence: 83%

“…The search for matches to this position-specific weight matrix was performed with the Asap software package 24 using a threshold of 0.8. As control, the HuR motif was shuffled 100 times.…”

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confidence: 99%

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

et al. 2012

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MicroRNAs are important regulators of gene expression in normal development and disease. miR-9 is overexpressed in several cancer forms, including brain tumours, hepatocellular carcinomas, breast cancer and Hodgkin lymphoma (HL). Here we demonstrated a relevance for miR-9 in HL pathogenesis and identified two new targets Dicer1 and HuR. HL is characterized by a massive infiltration of immune cells and fibroblasts in the tumour, whereas malignant cells represent only 1% of the tumour mass. These infiltrates provide important survival and growth signals to the tumour cells, and several lines of evidence indicate that they are essential for the persistence of HL. We show that inhibition of miR-9 leads to derepression of DICER and HuR, which in turn results in a decrease in cytokine production by HL cells followed by an impaired ability to attract normal inflammatory cells. Finally, inhibition of miR-9 by a systemically delivered antimiR-9 in a xenograft model of HL increases the protein levels of HuR and DICER1 and results in decreased tumour outgrowth, confirming that miR-9 actively participates in HL pathogenesis and points to miR-9 as a potential therapeutic target.Oncogene ( Keywords: miR-9; cytokines; Hodgkin lymphoma; HuR; DICER1 INTRODUCTIONChronic inflammation is a well-recognized cause of cancer and up to 25% of all cancers are thought to be induced by either chronic infections or autoimmune diseases. 1 Inflammation not only works as a tumour-promoting agent but also influences other steps of tumorigenesis by inducing DNA damage, angiogenesis, invasion and metastasis. 2 Hodgkin lymphoma (HL) is one of the most frequent lymphomas in the western world 3 and it can be divided in several subtypes based on the morphology, composition of the infiltrates and the phenotype of the immune cells. The nodular sclerosis subtype is the most common subtype of classical HL (cHL) and accounts for about 60--70% of the cHL cases, followed by mixed cellularity cHL accounting for 20--25%.cHL is an unusual B-cell malignancy in which the tumour cells represent only 1% of the tumour bulk, whereas the vast majority of the cells are a mixture of infiltrating immune cells and fibroblasts actively attracted via chemokine secretion by the malignant cells, the so-called Hodgkin and Reed --Sternberg cells. 3 Several lines of evidence indicate that the infiltrating cells are necessary for the survival of the HL cells by providing growth and survival signals, and protection from NK cells. 3,4 MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level by base-pairing to target mRNAs and promoting transcript instability and/or translational repression. 5 Mature miRNAs derive from long hairpin precursors that are sequentially processed by the RNase-III-type enzymes DROSHA and DICER1, respectively. 5 miRNAs have been implicated in several physiological and pathological events and can act as both tumour suppressors and oncogenes. 6

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“…Next, the Asap program (Marstrand et al 2008) was used to determine whether transcription factor-binding sites were overrepresented in the transiently acetylated regions. Furthermore, the search was narrowed based on the observation that a CEBP-binding site colocalizes with the transient acetylation near Pparg2 (Fig.…”

Section: Identification Of Gr and Cebpb At A Subset Of Genomic Regionmentioning

confidence: 99%

Propagation of adipogenic signals through an epigenomic transition state

Steger¹,

Grant²,

Schupp³

et al. 2010

Genes Dev.

218

221

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The transcriptional mechanisms by which temporary exposure to developmental signals instigates adipocyte differentiation are unknown. During early adipogenesis, we find transient enrichment of the glucocorticoid receptor (GR), CCAAT/enhancer-binding protein b (CEBPb), p300, mediator subunit 1, and histone H3 acetylation near genes involved in cell proliferation, development, and differentiation, including the gene encoding the master regulator of adipocyte differentiation, peroxisome proliferator-activated receptor g2 (PPARg2). Occupancy and enhancer function are triggered by adipogenic signals, and diminish upon their removal. GR, which is important for adipogenesis but need not be active in the mature adipocyte, functions transiently with other enhancer proteins to propagate a new program of gene expression that includes induction of PPARg2, thereby providing a memory of the earlier adipogenic signal. Thus, the conversion of preadipocyte to adipocyte involves the formation of an epigenomic transition state that is not observed in cells at the beginning or end of the differentiation process. Transcription factors control cell fate decisions by programming the expression of large gene sets, often through mechanisms impacting the post-translational modification of histone proteins in chromatin (Allis et al. 2007). Genome-wide changes to histone modification patterns occur as cells differentiate, such that distinct epigenomes are present in different cell types (Bernstein et al. 2007). A cell's epigenome is thought to be involved in establishing its identity, yet whether histone modifications transmit the memory of a given cell state or implement the memory once it is transmitted by a distinct mechanism is currently unclear.The epigenomic factors controlling adipocyte cell differentiation are not known. Adipocytes, the major fatcontaining component of adipose tissue, are terminally differentiated cells derived from mesenchymal precursors (Ailhaud et al. 1992). Study of adipocyte precursors in vivo is difficult because adipose tissue in rodents is undetectable macroscopically until shortly before birth.Thus, most of what is known about the molecular basis of adipocyte differentiation derives from tissue culture models, one of the best characterized being the mouse 3T3-L1 model Kehinde 1975, 1976). Temporary exposure to a mix of insulin, glucocorticoid, and an inducer of cAMP signaling triggers adipogenesis, changing the expression of hundreds of genes, including a variety of transcription factors that regulate one another as well as structural genes (Farmer 2006). One of these encodes peroxisome proliferator-activated receptor g (PPARg), a sequence-specific transcription factor that is necessary (Barak et al. 1999;Kubota et al. 1999;Rosen et al. 1999) and sufficient (Tontonoz et al. 1994;Hu et al. 1995;Shao and Lazar 1997) for adipogenesis, and is hence termed the master regulator (Rosen et al. 2002). CCAAT/ enhancer-binding protein (CEBP) transcriptional regulators also play a major role, and each can induce adip...

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Asap: A Framework for Over-Representation Statistics for Transcription Factor Binding Sites

Cited by 35 publications

References 25 publications

The genome landscape of ERα- and ERβ-binding DNA regions

The genome landscape of ERα- and ERβ-binding DNA regions

Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

Propagation of adipogenic signals through an epigenomic transition state

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