Dynamics and Regulatory Roles of RNA m⁶A Methylation in Unbalanced Genomes

N⁶-methyladenosine (m⁶A) in eukaryotic RNA is an epigenetic modification that is critical for RNA metabolism, gene expression regulation, and the development of organisms. Aberrant expression of m⁶A components appears in a variety of human diseases. RNA m⁶A modification in Drosophila has proven to be involved in sex determination regulated by Sxl and may affect X chromosome expression through the MSL complex. The dosage-related effects under the condition of genomic imbalance (i.e., aneuploidy) are related to various epigenetic regulatory mechanisms. Here, we investigated the roles of RNA m⁶A modification in unbalanced genomes using aneuploid Drosophila. The results showed that the expression of m⁶A components changed significantly under genomic imbalance, and affected the abundance and genome-wide distribution of m⁶A, which may be related to the developmental abnormalities of aneuploids. The relationships between methylation status and classical dosage effect, dosage compensation, and inverse dosage effect were also studied. In addition, we demonstrated that RNA m⁶A methylation may affect dosage-dependent gene regulation through dosage-sensitive modifiers, alternative splicing, the MSL complex, and other processes. More interestingly, there seems to be a closely relationship between MSL complex and RNA m⁶A modification. It is found that ectopically overexpressed MSL complex, especially the levels of H4K16Ac through MOF could influence the expression levels of m⁶A modification and genomic imbalance may be involved in this interaction. We found that m⁶A could affect the levels of H4K16Ac through MOF, a component of the MSL complex, and that genomic imbalance may be involved in this interaction. Altogether, our work reveals the dynamic and regulatory role of RNA m⁶A modification in unbalanced genomes, and may shed new light on the mechanisms of aneuploidy-related developmental abnormalities and diseases.