Abstract
Haploinsufficiency 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.
Highlights
Haploinsufficiency and aneuploidy are two phenomena, where gene dosage alterations cause severe defects resulting in developmental failures and disease
dosage compensation (DC) is mediated by the male-specific lethal complex (MSLc), which consists of the proteins MSL1, MSL2, MSL3, MOF, and two functionally redundant non-coding RNAs (ncRNAs) roX1 and roX2
In order to better understand the regulatory networks orchestrated by the Male-Specific Lethal complex (MSLc) members in vivo, we decided to comprehensively explore the DNA and RNA interaction network of MSL2 and MLE in Drosophila L3 larvae
Summary
Haploinsufficiency and aneuploidy are two phenomena, where gene dosage alterations cause severe defects resulting in developmental failures and disease. 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. DC is mediated by the male-specific lethal complex (MSLc), which consists of the proteins MSL1, MSL2, MSL3, MOF, and two functionally redundant ncRNAs roX1 and roX2. Incorporation of those into the core MSLc requires the activity of the RNA-associated RNA helicase MLE. We find that this gene-by-gene dosage compensation mechanism is conserved in mammalian cells and represents a presumably ancient function of the core MSLc. Taken together, we propose that the regulatory role of MSL2 extends beyond Xlinked genes and involves regulation of dosage-sensitive genes on autosomes
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