Sex Chromosome Dosage Compensation

Abstract

Organisms that use a chromosome‐based mechanism for sex determination must contend with the resulting sex‐linked gene dosage imbalance between males and females. While some organisms appear to tolerate gene‐dosage differences, others have evolved compensatory processes. The molecular mechanisms behind dosage compensation are only understood in a few organisms. In the fruit fly Drosophila melanogaster , XY males upregulate X‐linked gene expression two‐fold by a process that involves histone acetylation. Whether other lineages upregulate the male X is currently highly debated. Then in mammals, XX females inactivate one of their two X chromosomes using the long noncoding RNA Xist and repressive chromatin modifications. In the nematode Caenorhabditis elegans , XX hermaphrodites downregulate gene expression from both X chromosomes two‐fold by the action of a protein complex resembling the mitotic chromosome compaction machinery. Detailed studies of these mechanisms provided insights into not just dosage compensation, but the broader field of gene regulation in general. Key Concepts Differences in sex chromosome dose create a gene expression imbalance. Some lineages tolerate sex‐chromosome‐linked imbalances, other lineages evolved mechanisms to compensate for the differences in gene dosage. Complete balance includes balancing the single male X to autosomes and equalising sex‐linked gene dosage between the sexes. The MSL complex binds to the X chromosome in male Drosophila to upregulate gene expression two‐fold. The MSL subunit MOF acetylates lysine 16 on histone H4 in gene bodies, leading to enhancement of transcription elongation. The noncoding RNA Xist is expressed from the inactive X chromosome of female mammals. Xist RNA recruits chromatin‐modifying activities to transcriptionally silence the chromosome. The condensin‐like DCC binds both X chromosomes of hermaphroditic nematodes to dampen gene expression two‐fold. The DCC remodels and compacts the chromosome and recruits histone‐modifying enzymes to limit RNA Polymerase II loading onto the chromosomes.