Chromosome structure in Drosophila is determined by boundary pairing not loop extrusion

• Published in: eLife Vol. 13
• Main Authors: Bing, Xinyang, Ke, Wenfan, Fujioka, Miki, Kurbidaeva, Amina, Levitt, Sarah, Levine, Mike, Schedl, Paul, Jaynes, James B
• Format: Journal Article
• Language: English
• Published: Cambridge eLife Science Publications, Ltd 07.08.2024; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Boundaries; boundary elements; boundary:boundary pairing; Chromatin; Chromosomes; Chromosomes and Gene Expression; Cohesin; cohesin loop extrusion; Drosophila; gene activation; Genetic aspects; Insects; loop topology; Physiological aspects; Structure; TADs; United States
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.94070

Two different models have been proposed to explain how the endpoints of chromatin looped domains (‘TADs’) in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop. In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized, and experimental manipulations of the even skipped TAD boundary, homie , to test the predictions of the ‘loop-extrusion’ and the ‘boundary-pairing’ models. Our findings are incompatible with the loop-extrusion model, and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely to require loop extrusion.