Molecular Biology Select

The basic unit of chromatin is the nucleosome—about 146 basepairs of DNA wrapped around an octamer of his-tone proteins. A number of different posttranslational modifications to histones, such as methylation or acetyla-tion, regulate access to the DNA, allowing vital processes including transcription and DNA repair to take place. In this Molecular Biology Select, I discuss recent findings that reveal how certain histone modifications can be reversed and how some of these epigenetic marks depend on one another. The emerging picture is that even a stable , heritable chromatin state may include some remarkably dynamic and reversible features. The lysine residues of histone proteins can be mono-, di-, or trimethylated, signaling either transcriptional activation or repression depending on which lysine residue is methylated and to what extent. Histone methylation was considered a stable modification until the recent discovery that an amine oxidase called LSD1/BHC110 is able to de-methylate the lysine 4 of histone H3. Now, Tsukada et al. describe a new family of histone demethylases containing the so-called JmjC domain as their signature motif. They purified JHDM1 (for JmjC domain containing histone de-methylase 1) from extracts of HeLa cells and demonstrated in vitro that JHDM1 specifically demethylates lysine 36 of histone H3 with a preference for the dimethylated form. Dimethylated lysine 36 also may be the relevant substrate in vivo given that overexpression of JHDM1 in cells results in a decrease in dimethylated lysine 36 but not in the mono-or trimethylated forms. These findings are important for several reasons. The JmjC family of oxidases is larger than the LSD1 family and could include dedicated enzymes that reverse the wide variety of known histone methylation marks. In addition, proteins containing JmjC motifs, unlike LSD1, are present in budding yeast. In fact, the budding yeast JHDM1 homolog also demethylates lysine 36 of H3, establishing that histone demethylation is likely to be a general feature of eukaryotic chromatin. Finally, unlike LSD1, the JmjC-dependent reaction mechanism does not require a protonated amino group intermediate. Thus, JmjC enzymes could, at least in principle, target trimethylated lysines, such as the characteristic heterochromatin marks on lysine 9 or lysine 27 of histone H3. It remains to be seen whether any of the JmjC oxidases are specific for trimethylated lysines. Methylation of lysine 36 occurs in actively transcribed genes and helps to prevent spurious transcription from within open reading frames. Future studies should reveal whether lysine 36 demethylation controls …