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Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

ABSTRACT: Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs for gene regulatory functions and suggest that UCE sequence invariance originates from their combinatorial roles in gene control. We also note that the gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs). In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than the expected to simultaneously include protein-coding sequence, TF-binding sites, splice sites, and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation. Furthermore, we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information. Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa.

SUBMITTER: Warnefors M

PROVIDER: S-EPMC4989106 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

Warnefors Maria M Hartmann Britta B Thomsen Stefan S Alonso Claudio R CR

Molecular biology and evolution 20160531 9

Ultraconserved elements (UCEs) are discrete genomic elements conserved across large evolutionary distances. Although UCEs have been linked to multiple facets of mammalian gene regulation their extreme evolutionary conservation remains largely unexplained. Here, we apply a computational approach to investigate this question in Drosophila, exploring the molecular functions of more than 1,500 UCEs shared across the genomes of 12 Drosophila species. Our data indicate that Drosophila UCEs are hubs fo ...[more]

PMID: 27247329

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Project description:BackgroundSequence features in promoter regions are involved in regulating gene transcription initiation. Although numerous computational methods have been developed for predicting transcriptional start sites (TSSs) or transcription factor (TF) binding sites (TFBSs), they lack annotations for do not consider some important regulatory features such as CpG islands, tandem repeats, the TATA box, CCAAT box, GC box, over-represented oligonucleotides, DNA stability, and GC content. Additionally, the combinatorial interaction of TFs regulates the gene group that is associated with same expression pattern. To investigate gene transcriptional regulation, an integrated system that annotates regulatory features in a promoter sequence and detects co-regulation of TFs in a group of genes is needed.ResultsThis work identifies TSSs and regulatory features in a promoter sequence, and recognizes co-occurrence of cis-regulatory elements in co-expressed genes using a novel system. Three well-known TSS prediction tools are incorporated with orthologous conserved features, such as CpG islands, nucleotide composition, over-represented hexamer nucleotides, and DNA stability, to construct the novel Gene Promoter Miner (GPMiner) using a support vector machine (SVM). According to five-fold cross-validation results, the predictive sensitivity and specificity are both roughly 80%. The proposed system allows users to input a group of gene names/symbols, enabling the co-occurrence of TFBSs to be determined. Additionally, an input sequence can also be analyzed for homogeneity of experimental mammalian promoter sequences, and conserved regulatory features between homologous promoters can be observed through cross-species analysis. After identifying promoter regions, regulatory features are visualized graphically to facilitate gene promoter observations.ConclusionsThe GPMiner, which has a user-friendly input/output interface, has numerous benefits in analyzing human and mouse promoters. The proposed system is freely available at http://GPMiner.mbc.nctu.edu.tw/.

Project description:BackgroundOligodendrocytes are specialized cells of the nervous system that produce the myelin sheaths surrounding the axons of neurons. Myelinating the axons increases the speed of nerve conduction and demyelination contributes to the pathology of neurodegenerative diseases such as multiple sclerosis. Oligodendrocyte differentiation is specified early in development by the expression of the basic-helix-loop-helix transcription factor Olig2 in the ventral region of the neural tube. Understanding how Olig2 expression is controlled is therefore essential for elucidating the mechanisms governing oligodendrocyte differentiation. A method is needed to identify potential regulatory sequences in the long stretches of adjacent non-coding DNA that flank Olig2.Methodology/principal findingsWe identified ten potential regulatory regions upstream of Olig2 based on a combination of bioinformatics metrics that included evolutionary conservation across multiple vertebrate genomes, the presence of potential transcription factor binding sites and the existence of ultraconserved elements. One of our computational predictions includes a region previously identified as the Olig2 basal promoter, suggesting that our criterion represented characteristics of known regulatory regions. In this study, we tested one candidate regulatory region for its ability to modulate the Olig2 basal promoter and found that it represses expression in undifferentiated embryonic stem cells.Conclusions/significanceThe regulatory region we identified modifies the expression regulated by the Olig2 basal promoter in a manner consistent with our current understanding of Olig2 expression during oligodendrocyte differentiation. Our results support a model in which constitutive activation of Olig2 by its basal promoter is repressed in undifferentiated cells by upstream repressive elements until that repression is relieved during differentiation. We conclude that the potential regulatory elements presented in this study provide a good starting point for unraveling the cis-regulatory logic that governs Olig2 expression. Future studies of the functionality of the potential regulatory elements we present will help reveal the interactions that govern Olig2 expression during development.

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Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

Publications

Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila.

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