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Dissecting the interplay of chromatin accessibility and enhancer activity

Boek - Dissertatie

Title: Dissecting the interplay of chromatin accessibility and enhancer activity Transcriptional enhancers function as docking platforms for combinations of transcription factors to control gene expression. However, it is not clear how the sequence of an enhancer determines nucleosome occupancy, transcription factor recruitment, and transcriptional activation in vivo. Using ATAC-seq across a panel of Drosophila inbred strains we found that SNPs affecting Grainyhead binding sites causally determine the accessibility of epithelial enhancers. We then show that functional Grh binding sites occur in sequences that have a high affinity for nucleosomes and that deletion or ectopic expression of Grh causes loss or gain of DNA accessibility, respectively. Interestingly, however, while Grh binding is necessary for enhancer activity, it is not sufficient to activate an enhancer. Finally, we show that human Grh homologs, GRHL1/2/3, function similarly. We conclude that Grh binding is necessary and sufficient for the opening of epithelial enhancers, but not for their activation. Our data support the model that complex spatiotemporal expression patterns are controlled by regulatory hierarchies in which a pioneer factor, such as Grh, establishes a tissue-specific accessible chromatin landscape upon which other factors can act.
Jaar van publicatie:2018
Toegankelijkheid:Closed