Combinatorial gene regulatory functions underlie ultraconserved elements in Drosophila

Warnefors, Maria, Hartmann, Britta, Thomsen, Stefan and Alonso, Claudio R (2016) Combinatorial gene regulatory functions underlie ultraconserved elements in Drosophila. Molecular Biology and Evolution, 33 (7). msw101. ISSN 0737-4038

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Ultraconserved elements (UCEs) are discrete genomic elemen
ts 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.

Item Type: Article
Keywords: ultraconserved elements UCEs alternative splicing epigenetic regulation transcriptional regulation Hox genes organismal development
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0447 Genes. Alleles. Genome
Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics > QH0470.A-Z Experimental organisms, A-Z > QH0470.D7 Drosophila
Depositing User: Claudio Alonso
Date Deposited: 05 Jul 2016 11:44
Last Modified: 06 Mar 2017 13:42

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The molecular regulation of Hox genes during animal developmentG0952WELLCOME TRUST098410/Z/12/Z