The spleen of the exhypoxic polycythemic mouse was employed as a model system to study the effect of erythropoietin on enzymes that chemically modify nuclear proteins. At selected time intervals after in vivo administration of erythropoietin, acetyltransferase and methyltransferase activity were measured in nuclei isolated from the spleens of treated mice. In addition, the incorporation of labeled methyl and acetate groups into individual histone proteins was also examined. A 36% increase in nuclear acetyltransferase activity was observed eight hours after administration of erythropoietin, whereas nuclear methyltransferase activity increased by 42% 24 hours after administration of the hormone. Selective acetylation or methylation of individual histone proteins was not observed, and it is concluded that activation of transcription by erythropoietin is not the result of acetylation or methylation of nuclear proteins.