Prediction of tissue-specific cis-regulatory sequences: application to the ascidian Ciona intestinalis and the anterior neurectoderm - TEL - Thèses en ligne Accéder directement au contenu
Thèse Année : 2009

Prediction of tissue-specific cis-regulatory sequences: application to the ascidian Ciona intestinalis and the anterior neurectoderm

Prédiction des séquences cis-regulatrices tissu-spécifiques: application à l'ascidie Ciona intestinalis et au neurectoderme antérieur

Résumé

The detection and annotation of cis-regulatory sequences is a difficult problem. There is currently no generally applicable experimental procedure or computational algorithm to identify the non-coding regions of the genome that serve to activate gene expression in a given cell type. The only indicator of cis-regulatory function is the conservation of a sequence in other genomes. Regions can then be tested one-by-one in transgenic assays but this is time-consuming in vertebrates. Only a limited number of these already validated cis-regulatory sequences have been curated in biological databases. One of the main advantages of the model organism Ciona intestinalis is that cis-regulatory tests can be conducted very easily and the result is observable after one day while the animal follows the chordate body plan. However, a sequence found to be active in this organism can currently not be mapped to genomes of other animals. In my thesis, I first established a procedure to rank combinations of short sequence motifs by their distribution around a set of genes. The better a combination matches around genes expressed in a certain tissue, the higher is its score. I applied this to an already characterized enhancer of C. intestinalis expressed in the anterior neurectoderm which had been found by systematic mutations to be composed of a duplicated structure. The results of my procedure indicated that duplicated GATTA-sites are an essential feature of cis-regulatory elements active in the anterior neurectoderm. Searching the genome for matches to this signature resulted in putative enhancers that drive a reporter gene in 50% of the cases in the anterior neurectoderm. This is a relatively high proportion compared to much more complex prediction approaches reported in the literature. In addition, I tried to improve the curation of already published cis-regulatory elements by extracting them automatically from the full text of the biological research articles. Thanks to the thriving open access publishing model and the improvement in experimental assays, more and more of this data is becoming available. Finally, I showed that in the absence of sequence alignments between vertebrates and C. intestinalis, one can nevertheless find a handful of loci with a very unusually conserved gene order. In these cases, the cis-regulatory search space is reduced to a set of introns, some of which were recently shown to harbor enhancers. Many of these loci have not been analyzed yet. Together, these computational approaches should lead to a better characterization of cis-regulatory sequences and pave the way for further experimental validations.
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Dates et versions

tel-00413501 , version 1 (04-09-2009)

Identifiants

  • HAL Id : tel-00413501 , version 1

Citer

Maximilian Häussler. Prediction of tissue-specific cis-regulatory sequences: application to the ascidian Ciona intestinalis and the anterior neurectoderm. Cellular Biology. Université Paris Sud - Paris XI, 2009. English. ⟨NNT : ⟩. ⟨tel-00413501⟩

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