Methylation of lysines within the H3 tail at position 4, 9, 27, 36 and 79 (K4, K9, K27, K36 and K79) is important for the regulation of transcription and has long been regarded as stable modifications defining the epigenetic program of the cell. Lysines can be mono-, di-, or tri-methylated by specific histone methyltransferases. Trimethylated K4, K36 and K79 are in general considered to be marks of actively transcribed regions, whereas trimethylated K9 and K27 on histone H3 and K20 on histone H4 are enriched on transcriptionally silenced genes. The polycomb repressive complex 2 (PRC2), whose catatlytic subunit is an oncogene, mediates transcriptional repression by catalyzing the di- and tri-methylation of K27 (H3K27me2/me3). The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis, stem-cell differentiation and cellular senescence indicates that histone demethylases specific for H3K27me3 may exist. Using combined biochemical and bioinformatic approaches we have identified the two JmjC-domain-containing proteins UTX and JMJD3 as being histone lysine demethylases with specificity towards H3K27me3. Data presenting their functional characterization and their role in development will be presented at the meeting. Moreover, we have recently obtained some very interesting results suggesting that the JMJD3 is involved in regulating the transcription of the important INK4A-ARF locus, and that it functions as a tumor suppressor gene. These results will also be presented.