Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases.
Histone methylation regulates chromatin structure, transcription, and epigenetic state of the cell. Histone methylation is dynamically regulated by histone methylases and demethylases such as LSD1 and JHDM1, which mediate demethylation of di- and monomethylated histones. It has been unclear whether demethylases exist that reverse lysine trimethylation. We show the JmjC domain-containing protein JMJD2A reversed trimethylated H3-K9/K36 to di- but not mono- or unmethylated products. Overexpression of JMJD2A but not a catalytically inactive mutant reduced H3-K9/K36 trimethylation levels in cultured cells. In contrast, RNAi depletion of the C. elegans JMJD2A homolog resulted in an increase in general H3-K9Me3 and localized H3-K36Me3 levels on meiotic chromosomes and triggered p53-dependent germline apoptosis. Additionally, other human JMJD2 subfamily members also functioned as trimethylation-specific demethylases, converting H3-K9Me3 to H3-K9Me2 and H3-K9Me1, respectively. Our finding that this family of demethylases generates different methylated states at the same lysine residue provides a mechanism for fine-tuning histone methylation.
Whetstine
Johnathan R
JR
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Nottke
Amanda
A
Lan
Fei
F
Huarte
Maite
M
Smolikov
Sarit
S
Chen
Zhongzhou
Z
Spooner
Eric
E
Li
En
E
Zhang
Gongyi
G
Colaiacovo
Monica
M
Shi
Yang
Y
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D002454:Cell Differentiation / Q000502:physiology; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D008239:Lysine / Q000378:metabolism*; D008540:Meiosis / Q000502:physiology; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D010089:Oxidoreductases, N-Demethylating; D051135:Rad51 Recombinase; C495148:rad-51 protein, C elegans; D008239:Lysine