Developmental regulation of Drosophila dosage compensation in a 3D genome context

Chromosomal dosage compensation (DC) restores the expression balance of X chromosome between sexes, and is realised in Drosophila by the coordination of enriched X-linked PionX, HAS sequence elements and 1.6883F satellites, resulting in doubling the transcription of X-linked genes in males. We hypothesize that DC must be finely tuned during development and ask what are the underlying molecular mechanisms in this work. To inspect this, we collect new and published histone modification and 3D genome data of sexed samples from embryos to adults of Drosophila. We find that at least 30% of the Drosophila genes are bound by the DC complex or characteristic H4K16ac modifications specifically in only one or more tissues, and they show a higher H3K27me3 binding level than the rest DC genes constitutively compensated throughout development. The chrX harbors developmentally increasing long-range contacts (LRCs) relative to autosomes, and specifically in males. Integrative analyses with DC genes and regulatory sequences show that HAS and housekeeping genes preferentially located at the chromatin domain boundaries form stable LRCs. While PionXs and 1.6883F only form LRCs with the developmentally regulated DC genes in embryos and testes. Our results indicate that the Drosophila male chrX is characterised by two types of stable and developmentally regulated LRCs coordinating the dosage compensation to the different functional background of genes.