The JMJD2 family of histone demethylases reverses lysine trimethylation on histone H3-K9 and H3-K36. The study shows that JMJD2A, a member of this family, specifically demethylates trimethylated H3-K9 and H3-K36, but not mono- or di-methylated forms. Overexpression of JMJD2A reduces trimethylation levels in cultured cells, while depletion of the C. elegans JMJD2A homolog increases trimethylation levels on meiotic chromosomes and triggers p53-dependent germline apoptosis. Other JMJD2 family members also function as trimethylation-specific demethylases. These findings suggest that the JMJD2 family generates different methylated states at the same lysine residue, providing a mechanism for fine-tuning histone methylation. The study highlights the dynamic regulation of histone methylation and the role of JMJD2 family proteins in chromatin structure and gene expression. The results also indicate that alterations in histone methylation may contribute to human diseases such as cancer. The study provides insights into the biological significance of histone methylation and demethylation, emphasizing their importance in chromatin biology and gene regulation.The JMJD2 family of histone demethylases reverses lysine trimethylation on histone H3-K9 and H3-K36. The study shows that JMJD2A, a member of this family, specifically demethylates trimethylated H3-K9 and H3-K36, but not mono- or di-methylated forms. Overexpression of JMJD2A reduces trimethylation levels in cultured cells, while depletion of the C. elegans JMJD2A homolog increases trimethylation levels on meiotic chromosomes and triggers p53-dependent germline apoptosis. Other JMJD2 family members also function as trimethylation-specific demethylases. These findings suggest that the JMJD2 family generates different methylated states at the same lysine residue, providing a mechanism for fine-tuning histone methylation. The study highlights the dynamic regulation of histone methylation and the role of JMJD2 family proteins in chromatin structure and gene expression. The results also indicate that alterations in histone methylation may contribute to human diseases such as cancer. The study provides insights into the biological significance of histone methylation and demethylation, emphasizing their importance in chromatin biology and gene regulation.