Subtle changes in motif positioning cause tissue-specific effects on robustness of an enhancer's activity

• Verfasst von: Erceg, Jelena [VerfasserIn]
• Verfasst von: Saunders, Timothy E. [VerfasserIn]
• Verfasst von: Girardot, Charles [VerfasserIn]
• Verfasst von: Devos, Damien [VerfasserIn]
• Verfasst von: Hufnagel, Lars [VerfasserIn]
• Verfasst von: Furlong, Eileen E. M. [VerfasserIn]
• Titel: Subtle changes in motif positioning cause tissue-specific effects on robustness of an enhancer's activity
• Verf.angabe: Jelena Erceg, Timothy E. Saunders, Charles Girardot, Damien P. Devos, Lars Hufnagel, Eileen E.M. Furlong
• E-Jahr: 2014
• Jahr: January 2, 2014
• Umfang: 16 S.
• Fussnoten: Gesehen am 11.05.2017
• Titel Quelle: Enthalten in: Public Library of SciencePLoS Genetics
• Ort Quelle: San Francisco, Calif. : Public Library of Science, 2005
• Jahr Quelle: 2014
• Band/Heft Quelle: 10(2014,1) Artikel-Nr.e1004060, 16 Seiten
• ISSN Quelle: 1553-7404
• DOI: doi:10.1371/journal.pgen.1004060
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: DNA-binding proteins
• Sach-SW: Drosophila melanogaster
• Sach-SW: Embryos
• Sach-SW: Gene expression
• Sach-SW: Heart
• Sach-SW: In situ hybridization
• Sach-SW: Mesoderm
• Sach-SW: Sequence motif analysis
• K10plus-PPN: 1558500375

Abstract

Author Summary Transcription is initiated through the binding of transcription factors (TFs) to specific motifs that are dispersed throughout the genome. Genomics methods have helped to discern which motifs for a TF are occupied and which are not, yet it is poorly understood why certain combinations of bound motifs, and not others, drive specific patterns of expression. Here, we take a bottom-up approach to address this question: We constructed simple, synthetic elements containing motifs for only one or two TFs in different orientations and integrated them into the Drosophila genome. By assessing when and where these elements drive expression, we could model specific rules governing tissue-specific enhancer activity. Despite the general importance of TF combinatorial interactions during development, elements with a single TF's motif were often sufficient to drive complex expression. By combining motifs for two factors, we observed non-additive expression in the heart. While the enhancer's activity could tolerate changes in motif spacing and orientation in many tissues, the robustness of heart expression was very sensitive to subtle sequence changes. These results highlight an important property of enhancers—as their readout is context-specific, so too are the effects of mutations within them, including small insertions that may alter a gene's expression in one tissue, but not in another.