The inverse dosage effect caused by chromosome number variations shows global consequences in genomic imbalance including sexual dimorphism and an X chromosome-specific response. To investigate the relationship of the MSL complex to genomic imbalance, we over-expressed MSL2 in autosomal and sex chromosomal aneuploids, and analyzed the different transcriptomes. Some candidate genes involved in regulatory mechanisms have also been tested during embryogenesis using TSA-FISH. Here we show that the de novo MSL complex assembled on the X chromosomes in females further reduced the global expression level on the basis of 2/3 down-regulation caused by the inverse dosage effect in trisomy through epigenetic modulations rather than induced dosage compensation. Plus, the sexual dimorphism effect in unbalanced genomes was further examined due to the pre-existing of the MSL complex in males. All these results demonstrate the dynamic functions of the MSL complex on global gene expression in different aneuploid genomes.