Histone modifications are major post-translational mechanisms responsible for regulation of gene transcription involved in cellular senescence. By using immunofluorescence and Western blot, we showed that the global acetylated levels of histone H3 and H4 were significantly reduced in both replicative and premature senescence of human embryonic lung fibroblasts. However the whole trimethylated level of histone H4 lysine 20 was higher in senescent cells. The alterations in the mRNA and protein levels of histone acetyltransferases (HATs), histone methyltransferase (HMT), and histone deacetylases (HDACs) indicate that differential expression exists between replicative and premature senescent cells. Meanwhile, the reduced activity of HDACs was accompanied by cellular senescence. By employing the quantitative chromatin immunoprecipitation assay in detecting specific histone modifications in senescence-related genes including p53 and p16, it was demonstrated that the mRNA expression of p53 was associated with increased H4 acetylation in replicative senescence and increased H4 acetylation and trimethylation of histone H3 at lysine 4 (H3K4me3) in premature senescence. Both acetylation and trimethylation of H3 were involved in replicative senescence, while the acetylation of histone H3 and H4 was predominant in premature senescence, contributing to the mRNA expression of p16. In summary, the global hypoacetylation of histone H3 and H4 and the hypertrimethylation of histone H4 lysine 20 account for epigenetic characteristics in senescence, controlled by HATs, HMT, and HDACs differentially between replicative and premature senescence. Taken together, these findings suggest that the specific histone modifications are involved in regulating the expression of genes related to senescence of human embryonic lung fibroblasts.