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

• Published in: Cell 2023-08, Vol.186 (18), p.3826-3844.e26
• Main Authors: Mohana, Giriram, Dorier, Julien, Li, Xiao, Mouginot, Marion, Smith, Rebecca C., Malek, Héléna, Leleu, Marion, Rodriguez, Daniel, Khadka, Jenisha, Rosa, Patrycja, Cousin, Pascal, Iseli, Christian, Restrepo, Simon, Guex, Nicolas, McCabe, Brian D., Jankowski, Aleksander, Levine, Michael S., Gambetta, Maria Cristina
• Format: Article
• Language: English
• Subjects: adhesion; Animals; Chromatin - genetics; chromosomal loop; Chromosomes, Insect; DNA Packaging; Drosophila; Drosophila - genetics; Drosophila Proteins; Gene Expression Regulation; gene regulation; genes; genome architecture; genome organization; Genome, Insect; Mammals - genetics; nervous system; Neurogenesis; neuron; Neurons; TAD; transcription; Transcription Factors
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.07.008

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. [Display omitted] •Meta-domains are specific associations of distant TADs in mature fly neurons•In meta-domains, meta-loops tether neuronal gene promoters and intergenic elements•Meta-loops enable megabase-range regulation of neuronal gene transcription•Dedicated transcription factors, such as CTCF and GAF, form individual meta-loops Topologically associating domains that are megabases apart form meta-domains in mature fly neurons to regulate neuronal gene transcription.