Context-dependent enhancer function revealed by targeted inter-TAD relocation

Christopher Chase Bolt (), Lucille Lopez-Delisle, Aurélie Hintermann, Bénédicte Mascrez, Antonella Rauseo, Guillaume Andrey and Denis Duboule ()
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Christopher Chase Bolt: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Lucille Lopez-Delisle: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Aurélie Hintermann: University of Geneva
Bénédicte Mascrez: University of Geneva
Antonella Rauseo: University of Geneva
Guillaume Andrey: University of Geneva
Denis Duboule: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The expression of some genes depends on large, adjacent regions of the genome that contain multiple enhancers. These regulatory landscapes frequently align with Topologically Associating Domains (TADs), where they integrate the function of multiple similar enhancers to produce a global, TAD-specific regulation. We asked if an individual enhancer could overcome the influence of one of these landscapes, to drive gene transcription. To test this, we transferred an enhancer from its native location, into a nearby TAD with a related yet different functional specificity. We used the biphasic regulation of Hoxd genes during limb development as a paradigm. These genes are first activated in proximal limb cells by enhancers located in one TAD, which is then silenced when the neighboring TAD activates its enhancers in distal limb cells. We transferred a distal limb enhancer into the proximal limb TAD and found that its new context suppresses its normal distal specificity, even though it is bound by HOX13 transcription factors, which are responsible for the distal activity. This activity can be rescued only when a large portion of the surrounding environment is removed. These results indicate that, at least in some cases, the functioning of enhancer elements is subordinated to the host chromatin context, which can exert a dominant control over its activity.

Date: 2022
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DOI: 10.1038/s41467-022-31241-3

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