Interchromosomal contacts between regulatory regions trigger stable transgenerational epigenetic inheritance in Drosophila

Non-genetic information can be inherited through the germline and maintained across generations by the process of Transgenerational Epigenetic Inheritance (TEI). TEI can be established by various triggering events, including transient genetic perturbations. In Drosophila, hemizygosity of the Fab-7 regulatory element leads to establishment of TEI at a homologous locus on another chromosome, resulting in heritable epigenetic differences in eye colour and in levels of the histone mark H3K27me3. Here, we investigate the mechanism by which hemizygosity of Fab-7 leads to establishment of TEI. By mutating transcription factor binding sites within two key regions of Fab-7, we demonstrate the importance of two proteins in the establishment and maintenance of TEI: GAGA-factor and Pleiohomeotic. We show that these proteins function by recruiting the Polycomb Repressive Complex 2 and by mediating interchromosomal chromatin contacts between Fab-7 and its homologous locus. Finally, we recapitulate these chromatin contacts using an in vivo synthetic biology system and show that chromatin contacts alone can establish TEI in the absence of hemizygosity. This work provides a mechanism by which hemizygosity of one locus can establish an epigenetic memory at another in trans through long-distance chromatin contacts. ### Competing Interest Statement The authors have declared no competing interest.