THE MOF ACETYLTRANSFERASE IS A GENE EXPRESSION MASTER REGULATOR ESSENTIAL FOR LIFE.

In Drosophila, the Histone Acetiletransferase MOF is included in two different complexes: the Male Specific Lethal (MSL) complex and the Non Specific Lethal (NSL) complex. MSL complex is responsible for chromosome wide transcriptional up-regulation of the single X chromosome in Drosophila males, a process called Dosage Compensation and necessary to compensate for the presence of two transcriptionally active X chromosomes in female flies. The NSL complex is instead responsible for regulation of target genes encoded both on the X chromosome and autosomes. In mammals, MOF and the members of both MSL and NSL complex are conserved with respect to their Drosophila orthologs. In contrast with Drosophila MOF, though, mammalian MOF activity is still not proven to play a role in genome wide transcription regulation. Data reported here, prove that depletion of MOF from cardiomyocytes of mice at perinatal stages induces sex-unspecific lethality as a result of the onset of severe cardiomyopathy. The phenotype is due to the accumulation of extensive fibrosis in the organ, resulting from disseminated cell death. Experiments conducted in Mouse Embryonic Fibroblasts (MEFs) of both sexes, revealed that upon MOF Knock-Out, cells accumulate in G2/M transition of the cell cycle and display a severely impaired nuclear morphology. Strikingly, such phenotypes combine in both sexes with a bulk transcriptional down-regulation of genes across the whole genome, without showing any X chromosomal regulation specificity. Taken together, these results describe mammalian MOF as a key regulator of basic biological processes, essential for life.