CiteULike: emptyhb's binding_sites_turnover

Frequent Gain and Loss of Functional Transcription Factor Binding Sites

Scott Doniger — 2007-05-26T03:59:06-00:00

PLoS Computational Biology, Vol. 3, No. 5. (1 May 2007), e99.

Cis-regulatory sequences are not always conserved across species. Divergence within cis-regulatory sequences may result from the evolution of species-specific patterns of gene expression or the flexible nature of the cis-regulatory code. The identification of functional divergence in cis-regulatory sequences is therefore important for both understanding the role of gene regulation in evolution and annotating regulatory elements. We have developed an evolutionary model to detect the loss of constraint on individual transcription factor binding sites (TFBSs). We find that a significant fraction of functionally constrained binding sites have been lost in a lineage-specific manner among three closely related yeast species. Binding site loss has previously been explained by turnover, where the concurrent gain and loss of a binding site maintains gene regulation. We estimate that nearly half of all loss events cannot be explained by binding site turnover. Recreating the mutations that led to binding site loss confirms that these sequence changes affect gene expression in some cases. We also estimate that there is a high rate of binding site gain, as more than half of experimentally identified S. cerevisiae binding sites are not conserved across species. The frequent gain and loss of TFBSs implies that cis-regulatory sequences are labile and, in the absence of turnover, may contribute to species-specific patterns of gene expression.

Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation

Emily Hare — 2008-06-27T18:46:42-00:00

PLoS Genet, Vol. 4, No. 6. (27 June 2008), e1000106.

The gene expression pattern specified by an animal regulatory sequence is generally viewed as arising from the particular arrangement of transcription factor binding sites it contains. However, we demonstrate here that regulatory sequences whose binding sites have been almost completely rearranged can still produce identical outputs. We sequenced the even-skipped locus from six species of scavenger flies (Sepsidae) that are highly diverged from the model species Drosophila melanogaster, but share its basic patterns of developmental gene expression. Although there is little sequence similarity between the sepsid eve enhancers and their well-characterized D. melanogaster counterparts, the sepsid and Drosophila enhancers drive nearly identical expression patterns in transgenic D. melanogaster embryos. We conclude that the molecular machinery that connects regulatory sequences to the transcription apparatus is more flexible than previously appreciated. In exploring this diverse collection of sequences to identify the shared features that account for their similar functions, we found a small number of short (20–30 bp) sequences nearly perfectly conserved among the species. These highly conserved sequences are strongly enriched for pairs of overlapping or adjacent binding sites. Together, these observations suggest that the local arrangement of binding sites relative to each other is more important than their overall arrangement into larger units of cis-regulatory function.

Large-scale turnover of functional transcription factor binding sites in Drosophila.

AM Moses — 2006-12-08T05:42:25-00:00

PLoS Comput Biol, Vol. 2, No. 10. (October 2006)

The gain and loss of functional transcription factor binding sites has been proposed as a major source of evolutionary change in cis-regulatory DNA and gene expression. We have developed an evolutionary model to study binding-site turnover that uses multiple sequence alignments to assess the evolutionary constraint on individual binding sites, and to map gain and loss events along a phylogenetic tree. We apply this model to study the evolutionary dynamics of binding sites of the Drosophila melanogaster transcription factor Zeste, using genome-wide in vivo (ChIP-chip) binding data to identify functional Zeste binding sites, and the genome sequences of D. melanogaster, D. simulans, D. erecta, and D. yakuba to study their evolution. We estimate that more than 5% of functional Zeste binding sites in D. melanogaster were gained along the D. melanogaster lineage or lost along one of the other lineages. We find that Zeste-bound regions have a reduced rate of binding-site loss and an increased rate of binding-site gain relative to flanking sequences. Finally, we show that binding-site gains and losses are asymmetrically distributed with respect to D. melanogaster, consistent with lineage-specific acquisition and loss of Zeste-responsive regulatory elements.

Shape and function of the Bicoid morphogen gradient in dipteran species with different sized embryos.

Thomas Gregor — 2008-03-28T22:31:11-00:00

Dev Biol (13 February 2008)

The Bicoid morphogen evolved approximately 150 MYA from a Hox3 duplication and is only found in higher dipterans. A major difference between dipteran species, however, is the size of the embryo, which varies up to 5-fold. Although the expression of developmental factors scale with egg length, it remains unknown how this scaling is achieved. To test whether scaling is accounted for by the properties of Bicoid, we expressed eGFP fused to the coding region of bicoid from three dipteran species in transgenic Drosophila embryos using the Drosophila bicoid cis-regulatory and mRNA localization sequences. In such embryos, we find that Lucilia sericata and Calliphora vicina Bicoid produce gradients very similar to the endogenous Drosophila gradient and much shorter than what they would have produced in their own respective species. The common shape of the Drosophila, Lucilia and Calliphora Bicoid gradients appears to be a conserved feature of the Bicoid protein. Surprisingly, despite their similar distributions, we find that Bicoid from Lucilia and Calliphora do not rescue Drosophila bicoid mutants, suggesting that that Bicoid proteins have evolved species-specific functional amino acid differences. We also found that maternal expression and anteriorly localization of proteins other than Bcd does not necessarily give rise to a gradient; eGFP produced a uniform protein distribution. However, a shallow gradient was observed using eGFP-NLS, suggesting nuclear localization may be necessary but not sufficient for gradient formation.

Rapid restructuring of bicoid-dependent hunchback promoters within and between Dipteran species: implications for molecular coevolution

Alistair Mcgregor — 2007-12-31T03:35:47-00:00

Evolution & Development, Vol. 3, No. 6. (2001), pp. 397-407.

SUMMARY Interacting genetic elements need to coevolve if their joint function is to be maintained; for example, the correct binding of transcriptional regulators to defined binding sites in gene promoters needs to be maintained during evolution to ensure proper function. As part of a wider investigation into the molecular coevolution of the Dipteran homeodomain-bearing regulator bicoid (bcd) and Bcd-dependent promoters, we present data on the functional, structural, and sequence differences between the promoters of the segmentation gene hunchback (hb), in several species of Cyclorrhaphan (higher) Diptera. The result of phenocopying hb mutations using RNA interference (RNAi) in Musca domestica shows broadly similar functions to the hb gene in Drosophila melanogaster. However, the Bcd-binding sites in the hb promoters of Drosophila, Musca, and the two blowfly species Lucilia sericata and Calliphora vicina differ in copy number, sequence, orientation, and spacing. Furthermore, all promoters are subject to rapid turnover by slippage-like processes leading to high densities of short repetitive motifs. A study of polymorphism among six strains of M. domestica reveals that turnover by slippage also occurs in the promoter, untranslated leader, and exonic coding sequences of hb, but to different extents. We discuss these results in terms of the known interspecific differences in bcd and the potential coevolution of selected compensatory mutations in trans and cis in response to continuous promoter restructuring.

Evolution of functionally conserved enhancers can be accelerated in large populations: a population-genetic model.

AJ Carter — 2007-12-11T20:54:55-00:00

Proc Biol Sci, Vol. 269, No. 1494. (7 May 2002), pp. 953-960.

The evolution of cis-regulatory elements (or enhancers) appears to proceed at dramatically different rates in different taxa. Vertebrate enhancers are often very highly conserved in their sequences, and relative positions, across distantly related taxa. In contrast, functionally equivalent enhancers in closely related Drosophila species can differ greatly in their sequences and spatial organization. We present a population-genetic model to explain this difference. The model examines the dynamics of fixation of pairs of individually deleterious, but compensating, mutations. As expected, small populations are predicted to have a high rate of evolution, and the rate decreases with increasing population size. In contrast to previous models, however, this model predicts that the rate of evolution by pairs of compensatory mutations increases dramatically for population sizes above several thousand individuals, to the point of greatly exceeding the neutral rate. Application of this model predicts that species with moderate population sizes will have relatively conserved enhancers, whereas species with larger populations will be expected to evolve their enhancers at much higher rates. We propose that the different degree of conservation seen in vertebrate and Drosophila enhancers may be explained solely by differences in their population sizes and generation times.

Evolution of Transcription Factor Binding Sites in Mammalian Gene Regulatory Regions: Conservation and Turnover

Emmanouil Dermitzakis — 2007-01-17T02:29:55-00:00

Mol Biol Evol, Vol. 19, No. 7. (1 July 2002), pp. 1114-1121.

Comparisons between human and rodent DNA sequences are widely used for the identification of regulatory regions (phylogenetic footprinting), and the importance of such intergenomic comparisons for promoter annotation is expanding. The efficacy of such comparisons for the identification of functional regulatory elements hinges on the evolutionary dynamics of promoter sequences. Although it is widely appreciated that conservation of sequence motifs may provide a suggestion of function, it is not known as to what proportion of the functional binding sites in humans is conserved in distant species. In this report, we present an analysis of the evolutionary dynamics of transcription factor binding sites whose function had been experimentally verified in promoters of 51 human genes and compare their sequence to homologous sequences in other primate species and rodents. Our results show that there is extensive divergence within the nucleotide sequence of transcription factor binding sites. Using direct experimental data from functional studies in both human and rodents for 20 of the regulatory regions, we estimate that 32%-40% of the human functional sites are not functional in rodents. This is evidence that there is widespread turnover of transcription factor binding sites. These results have important implications for the efficacy of phylogenetic footprinting and the interpretation of the pattern of evolution in regulatory sequences.