Highlights d Identification of genomic buttons that drive homologous chromosome pairing in flies d DNA regions spanning TADs display button activity, but not all buttons contain TADs d Button-driven homologous pairing is necessary but not sufficient for transvection d Homologous chromosome pairing and transvection are celltype-specific

Homologous chromosomes colocalize to regulate gene expression in processes including genomic imprinting and X-inactivation, but the mechanisms driving these interactions are poorly understood. In Drosophila, homologous chromosomes pair throughout development, promoting an interchromosomal gene regulatory mechanism called transvection. Despite over a century of study, the molecular features that drive chromosome-wide pairing and transvection are unknown. Here, we find that the ability to pair with a homologous sequence is not a general feature of all loci, but is specific to "button" loci interspersed across the genome. Buttons are characterized by topologically associated domains (TADs), which drive pairing with their endogenous loci from multiple genomic locations. Using a button spanning the spineless gene as a paradigm, we find that pairing is necessary but not sufficient for transvection. spineless pairing and transvection are cell-type-specific, suggesting that local buttoning and unbuttoning regulates transvection efficiency between cell types. Together, our data support a model in which button loci bring homologous chromosomes together to facilitate cell-type-specific interchromosomal gene regulation.

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