Facultative dosage compensation of developmental genes on autosomes in Drosophila and mouse embryonic stem cells

• DOI: 10.1038/s41467-018-05642-2
• Publication Date: 2018-09-03T09:02:47Z
• Authors: Claudia Isabelle ...; M. Felicia Basili...; Giuseppe Semplicio; Plamen Georgiev; Noel Marie Gutierrez; Asifa Akhtar
• Keywords: Male; Science; Article; Mice; 03 medical and health sciences; Dosage Compensation, Genetic; Animals; Drosophila Proteins; Wings, Animal; Compound Eye, Arthropod; Genes, Developmental; Cells, Cultured; Embryonic Stem Cells; Body Patterning; Mice, Knockout; 0303 health sciences; Q; Gene Expression Regulation, Developmental; Nuclear Proteins; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Larva; Drosophila; Female; Transcription Factors

AbstractHaploinsufficiency and aneuploidy are two phenomena, where gene dosage alterations cause severe defects ultimately resulting in developmental failures and disease. One remarkable exception is the X chromosome, where copy number differences between sexes are buffered by dosage compensation systems. In Drosophila, the Male-Specific Lethal complex (MSLc) mediates upregulation of the single male X chromosome. The evolutionary origin and conservation of this process orchestrated by MSL2, the only male-specific protein within the fly MSLc, have remained unclear. Here, we report that MSL2, in addition to regulating the X chromosome, targets autosomal genes involved in patterning and morphogenesis. Precise regulation of these genes by MSL2 is required for proper development. This set of dosage-sensitive genes maintains such regulation during evolution, as MSL2 binds and similarly regulates mouse orthologues via Histone H4 lysine 16 acetylation. We propose that this gene-by-gene dosage compensation mechanism was co-opted during evolution for chromosome-wide regulation of the Drosophila male X.