Abstract
Developmental genes can harbour multiple transcriptional enhancers that act simultaneously or in succession to achieve robust and precise spatiotemporal expression. However, the mechanisms underlying cooperation between cis-acting elements are poorly documented, notably in vertebrates. The mouse gene Krox20 encodes a transcription factor required for the specification of two segments (rhombomeres) of the developing hindbrain. In rhombomere 3, Krox20 is subject to direct positive feedback governed by an autoregulatory enhancer, element A. In contrast, a second enhancer, element C, distant by 70 kb, is active from the initiation of transcription independent of the presence of the KROX20 protein. Here, using both enhancer knock-outs and investigations of chromatin organisation, we show that element C possesses a dual activity: besides its classical enhancer function, it is also permanently required in cis to potentiate the autoregulatory activity of element A, by increasing its chromatin accessibility. This work uncovers a novel, asymmetrical, long-range mode of cooperation between cis-acting elements that might be essential to avoid promiscuous activation of positive autoregulatory elements.
Highlights
DNA cis-acting elements play key roles in the regulation and evolution of gene expression by controlling spatiotemporal transcription patterns
The activation of specific genes is governed by regulatory DNA sequences present nearby on the chromosome
We study two enhancers governing the expression of a gene involved in the formation of the posterior brain in vertebrates
Summary
DNA cis-acting elements play key roles in the regulation and evolution of gene expression by controlling spatiotemporal transcription patterns. This approach is helpful in the analysis of multiple enhancers controlling the same gene [7], but can be challenging for the study of mammalian enhancer that are located far away from the promoter that they control These different approaches provide useful information on spatial and temporal activity of the putative enhancer element, but they usually do not establish whether and how the enhancer participates in the control of the expression of its suspected cognate gene in its full normal genomic context. Answer to this latter question requires in vivo analyses involving deletion or mutation of the endogenous enhancer.
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