An international team of researchers from the University of Lausanne, EPFL, Princeton University and the University of Warsaw described a new mechanism of genome folding in fruit flies. The results of the study were published in the prestigious journal “Cell”.

Genome carries in DNA the complete genetic information of an organism, including genes and their regulatory elements. The interpretation of this information occurs within a complex three-dimensional genome folding architecture in the cell nucleus that shapes chromosomes to bring regulatory elements into spatial proximity of their target genes.

The 3D organisation of the genome spans multiple scales, including well-demarcated physically interacting domains, known as Topologically Associated Domains (TADs). Previous research identified TADs as the basic units of genome organisation in many species, ranging from yeast to human.

A team of researchers led by Prof. Maria Cristina Gambetta from the University of Lausanne, Dr Aleksander Jankowski from the Institute of Informatics, University of Warsaw and Prof. Michael S. Levine from Princeton University presented in the journal “Cell” evidence of a previously unreported level of genome folding.

They found that in the nervous system of fruit fly Drosophila melanogaster, distant pairs of TADs interact across distances as long as half a chromosome, forming so-called meta-domains. Within these meta-domains, specific gene promoters and regulatory elements are paired together, even though they are located tens of TADs away as measured along the chromosome. The genes associated with these meta-loops encode important neuronal determinants, including those engaged in axonal guidance and adhesion.

“Remarkably, meta-loops show a high degree of evolutionary conservation across two remote fly species. The ends of these meta-loops recognise each other despite the difference in genomic distances between matching genomic loci in the two species,” Dr Aleksander Jankowski from the Institute of Informatics at the University of Warsaw says.

The researchers envisaged that meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances, and experimentally showed that two such factors, GAF and CTCF, play direct roles in this process. An important observation is the relative simplicity of the meta-domain interactions in fruit flies, compared with those previously described in mammals.

The results of the study highlight the significance of this long-range genome folding in regulating the transcription of neuronal genes. The authors of the paper in “Cell” hypothesise that genomes can fold into many highly specialised scaffolds that enable long-range regulatory interactions.