Calcium Homeostasis Is Involved in the Modulation of Gene Expression by MSL2 in Imbalanced Genomes

Aneuploidy is highly detrimental to organisms due to genomic imbalance. However, the influence of parental unbalanced genome conditions on gene expression of their offspring remains unclear, particularly in animals. To further explore the molecular regulatory mechanisms, we firstly analyzed the expression patterns of aneuploid <i>Drosophila</i> offspring from different parents with unbalanced genomes via reciprocal crosses and studied the potential functions of male-specific lethal 2 (MSL2) in this process. The results showed that the ectopic expression of MSL2 in aneuploidy resulted in gene expression patterns closer to those of diploidy, including MSL2 target genes, maternal genes, mitochondrial genes, and transposable elements. In addition, it was also found that <i>ERp60</i>, the key target gene of MSL2, played a crucial role in regulating endoplasmic reticulum (ER) Ca²⁺ homeostasis through its interaction with the STIM1 protein. When it was overexpressed, ER Ca²⁺ levels and the survival of aneuploid females were significantly increased. Furthermore, we observed upregulated ER Ca²⁺ levels identified in aneuploid brains, which suggested that Ca²⁺ homeostasis may be involved in the regulation mediated by MSL2 in aneuploid genomes.