The study investigates the role of the JMJD2 family of histone demethylases in reversing lysine trimethylation. Specifically, it focuses on the JmjC domain-containing protein JMJD2A, which is shown to reverse trimethylated H3-K9/K36 to di-methylated products but not mono- or unmodified forms. Overexpression of JMJD2A reduces H3-K9/K36 trimethylation levels in cultured cells, while RNAi depletion of the C. elegans JMJD2A homolog (ceJMJD2) increases H3-K9/K36 trimethylation levels and triggers p53-dependent germline apoptosis. The study also demonstrates that other human JMJD2 family members, including JMJD2C and JMJD2D, are primarily trimethyl-specific histone demethylases. These findings provide evidence that the JMJD2 family plays a crucial role in fine-tuning histone methylation and may have important biological functions in multicellular organisms.The study investigates the role of the JMJD2 family of histone demethylases in reversing lysine trimethylation. Specifically, it focuses on the JmjC domain-containing protein JMJD2A, which is shown to reverse trimethylated H3-K9/K36 to di-methylated products but not mono- or unmodified forms. Overexpression of JMJD2A reduces H3-K9/K36 trimethylation levels in cultured cells, while RNAi depletion of the C. elegans JMJD2A homolog (ceJMJD2) increases H3-K9/K36 trimethylation levels and triggers p53-dependent germline apoptosis. The study also demonstrates that other human JMJD2 family members, including JMJD2C and JMJD2D, are primarily trimethyl-specific histone demethylases. These findings provide evidence that the JMJD2 family plays a crucial role in fine-tuning histone methylation and may have important biological functions in multicellular organisms.