Usp21 deubiquitinates histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Deubiquitination of histone H2A releaves the repression of di- and trimethylation of histone H3 at 'Lys-4', resulting in regulation of transcriptional initiation. Usp21 regulates gene expression via histone H2A deubiquitination. It is also capable of removing NEDD8 from NEDD8 conjugates but has no effect on Sentrin-1 conjugates.