Cell.: auth.: group Gambetta

Cell. 2023 Jul 25;S0092-8674(23)00741-9.

 doi: 10.1016/j.cell.2023.07.008. Online ahead of print.

Chromosome-level organization of the regulatory genome in the Drosophila nervous system

Giriram Mohana 1Julien Dorier 2Xiao Li 3Marion Mouginot 1Rebecca C Smith 4Héléna Malek 1Marion Leleu 2Daniel Rodriguez 1Jenisha Khadka 1Patrycja Rosa 5Pascal Cousin 1Christian Iseli 2Simon Restrepo 6Nicolas Guex 2Brian D McCabe 4Aleksander Jankowski 7Michael S Levine 8Maria Cristina Gambetta 9


Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.

Keywords: Drosophila; TAD; chromosomal loop; gene regulation; genome architecture; genome organization; nervous system; neuron; transcription.