@article {49092, title = {Comprehensive analysis of a cis-regulatory region reveals pleiotropy in enhancer function.}, journal = {Cell Reports}, volume = {22}, year = {2018}, month = {2018 Mar 13}, pages = {3021-3031}, abstract = {

Developmental genes can have complex cis-regulatory regions with multiple enhancers. Early work revealed remarkable modularity of enhancers, whereby distinct DNA regions drive gene expression in defined spatiotemporal domains. Nevertheless, a few reports have shown that enhancers function in multiple developmental stages, implying that enhancers can be pleiotropic. Here, we have studied the activity of the enhancers of the shavenbaby gene throughout D.\ melanogaster development. We found that all seven shavenbaby enhancers drive expression in multiple tissues and developmental stages. We explored how enhancer pleiotropy is encoded in two of these enhancers. In one enhancer,\ the same transcription factor binding sites contribute to embryonic and pupal expression, revealing site pleiotropy, whereas for a second enhancer, these roles are encoded by distinct sites. Enhancer pleiotropy may be a common feature of cis-regulatory regions of developmental genes, and site pleiotropy may constrain enhancer evolution in some cases.

}, issn = {2211-1247}, doi = {10.1016/j.celrep.2018.02.073}, author = {Preger-Ben Noon, Ella and Sabar{\'\i}s, Gonzalo and Ortiz, Daniela M and Sager, Jonathan and Liebowitz, Anna and Stern, David L and Frankel, Nicol{\'a}s} } @article {49452, title = {Pleiotropy in enhancer function is encoded through diverse genetic architectures.}, journal = {bioRxiv}, year = {2017}, month = {2017 Sep 14}, abstract = {

Developmental genes can have complex cis-regulatory regions, with multiple enhancers scattered across stretches of DNA spanning tens or hundreds of kilobases. Early work revealed remarkable modularity of enhancers, where distinct regions of DNA, bound by combinations of transcription factors, drive gene expression in defined spatio-temporal domains. Nevertheless, a few reports have shown that enhancer function may be required in multiple developmental stages, implying that regulatory elements can be pleiotropic. In these cases, it is not clear whether the pleiotropic enhancers employ the same transcription factor binding sites to drive expression at multiple developmental stages or whether enhancers function as chromatin scaffolds, where independent sets of transcription factor binding sites act at different stages. In this work we have studied the activity of the enhancers of the shavenbaby gene throughout D. melanogaster development. We found that all seven shavenbaby enhancers drive gene expression in multiple tissues and developmental stages at varying levels of redundancy. We have explored how this pleiotropy is encoded in two of these enhancers. In one enhancer, the same transcription factor binding sites contribute to embryonic and pupal expression, whereas for a second enhancer, these roles are largely encoded by distinct transcription factor binding sites. Our data suggest that enhancer pleiotropy might be a common feature of cis-regulatory regions of developmental genes and that this pleiotropy can be encoded through multiple genetic architectures.

}, doi = {10.1101/188532}, author = {Preger-Ben Noon, Ella and Sabar{\'\i}s, Gonzalo and Ortiz, Daniela M and Sager, Jonathan and Liebowitz, Anna and Stern, David L and Frankel, Nicol{\'a}s} } @article {48043, title = {Evolved repression overcomes enhancer robustness.}, journal = {Developmental Cell}, volume = {39}, year = {2016}, month = {2016 Nov 10}, pages = {572-84}, abstract = {

Biological systems display extraordinary robustness. Robustness of transcriptional enhancers results mainly from clusters of binding sites for the same transcription factor, and it is not clear how robust enhancers can evolve loss of expression through point mutations. Here, we report the high-resolution functional dissection of a robust enhancer of the\ shavenbaby\ gene that has contributed to morphological evolution. We found that robustness is encoded by many binding sites for the transcriptional activator Arrowhead and that, during evolution, some of these activator sites were lost, weakening enhancer activity. Complete silencing of enhancer function, however, required evolution of a binding site for the spatially restricted potent repressor Abrupt. These findings illustrate that recruitment of\ repressor binding sites can overcome enhancer robustness and may minimize pleiotropic consequences of enhancer evolution. Recruitment of repression may be a general mode of evolution to break robust regulatory linkages.

}, doi = {10.1016/j.devcel.2016.10.010}, author = {Preger-Ben Noon, Ella and Davis, Fred P and Stern, David L} } @article {47264, title = {The soft touch: low-affinity transcription factor binding sites in development and evolution.}, journal = {Current Topics in Developmental Biology}, year = {2016}, month = {2016 Jan 07}, abstract = {

Transcription factor proteins regulate gene expression by binding to specific DNA regions. Most studies of transcription factor binding sites have focused on the highest affinity sites for each factor. There is abundant evidence, however, that binding sites with a range of affinities, including very low affinities, are critical to gene regulation. Here, we present the theoretical and experimental evidence for the importance of low-affinity sites in gene regulation and development. We also discuss the implications of the widespread use of low-affinity sites in eukaryotic genomes for robustness, precision, specificity, and evolution of gene regulation.

}, doi = {10.1016/bs.ctdb.2015.11.018}, author = {Crocker, Justin and Preger-Ben Noon, Ella and Stern, David L} } @article {47055, title = {Evolving genital structures: A deep look at network co-option.}, journal = {Developmental Cell}, volume = {34}, year = {2015}, month = {2015 Sep 14}, pages = {485-6}, abstract = {

Novel body structures are often generated by the redeployment of ancestral components of the genome. In this issue of Developmental Cell, Glassford et\ al. (2015) present a thorough analysis of the co-option of a gene regulatory network in the origin of an evolutionary novelty.

}, issn = {1878-1551}, doi = {10.1016/j.devcel.2015.08.022}, author = {Preger-Ben Noon, Ella and Frankel, Nicol{\'a}s} }