Regulating gene expression in 3D: a view from Drosophila embryogenesis

In multicellular organisms, embryonic development requires the coordinated expression of genes in both a temporal- and tissue-specific manner. This complex regulation is controlled by the binding of sequence-specific transcription factors to enhancer elements, which can be located at great distances from their target gene. Chromatin conformation studies have shown that gene activation by remote enhancers is associated with the establishment of a chromatin loop. However, our previous work indicates that enhancer-promoter loops are often formed prior to transcription, suggesting that chromatin loops are necessary, but not sufficient, for gene activation (Ghavi-Helm et al. Nature 2014). The precise link between chromatin organization and transcription regulation remains therefore unclear. In order to resolve the interplay between chromatin loops and the regulation of gene expression, we studied the effects of major genomic rearrangements on both transcription and chromatin conformation. We took advantage of D. melanogaster lines with highly scrambled chromosomes, called balancer chromosomes, which are the product of multiple chromosomal rearrangements generated by X-ray mutagenesis. Thanks to this unique setup, we were able to analyze the functional impact of multiple large rearrangements such as translocations and inversions, but also of numerous smaller structural variants such as deletions. The results are revealing surprising insights into the relationship between chromatin topology in cis and transcriptional regulation (Ghavi-Helm et al. Nature Genetics 2019).

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Matt Humphries
The Cambridge Building - Petersfield Lecture Theatre