A high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivation

In mammalian female cells, nearly all genes are silenced on one of two X chromosomes. Heterozygous females with "dominant" X-linked diseases, such as Rett syndrome, may benefit from pharmacological reactivation of the silent, healthy allele in affected organs. Toward establishing proof of concept, here we carry out a primed screen of a large library of small molecules for compounds that can reactivate expression from the inactive X (Xi). We identify a combination of compounds that inhibits the DNA methylation and Aurora kinase pathways and demonstrate that the two pathways act synergistically to repress genes on the Xi, including genes involved in X-linked disease.