The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36

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Abstract
Post-translational modification of chromatin has profound effects on many biological processes including transcriptional regulation, heterochromatin organization, and X-chromosome inactivation1,2. Recent studies indicate that methylation on specific histone lysine (K) residues participates in many of these processes3. Lysine methylation occurs in three distinct states, having either one (me1), two (me2) or three (me3) methyl groups attached to the amine group of the lysine side chain. These differences in modification state have an important role in defining how methylated chromatin is recognized and interpreted4,5,6. Until recently, histone lysine methylation was considered a stable modification7,8, but the identification of histone demethylase enzymes has demonstrated the reversibility of this epigenetic mark9,10,11. So far, all characterized histone demethylases show enzymatic activity towards lysine residues modified in the me1 or me2 state9,10,11, leaving open the possibility that me3 constitutes an irreversible modification. Here we demonstrate that JHDM3A (jumonji C (JmjC)-domain-containing histone demethylase 3A; also known as JMJD2A) is capable of removing the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36). Overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin, indicating a role for JHDM3A in antagonizing methylated H3K9 nucleated events. siRNA-mediated knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of a JHDM3A target gene, ASCL2, indicating that JHDM3A may function in euchromatin to remove histone methylation marks that are associated with active transcription12.