The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing.
Epigenetic chromatin marks restrict the ability of differentiated cells to change gene expression programs in response to environmental cues and to transdifferentiate. Polycomb group (PcG) proteins mediate gene silencing and repress transdifferentiation in a manner dependent on histone H3 lysine 27 trimethylation (H3K27me3). However, macrophages migrated into inflamed tissues can transdifferentiate, but it is unknown whether inflammation alters PcG-dependent silencing. Here we show that the JmjC-domain protein Jmjd3 is a H3K27me demethylase expressed in macrophages in response to bacterial products and inflammatory cytokines. Jmjd3 binds PcG target genes and regulates their H3K27me3 levels and transcriptional activity. The discovery of an inducible enzyme that erases a histone mark controlling differentiation and cell identity provides a link between inflammation and reprogramming of the epigenome, which could be the basis for macrophage plasticity and might explain the differentiation abnormalities in chronic inflammation.
De Santa
Francesca
F
Department of Experimental Oncology, European Institute of Oncology, Campus IFOM-IEO, Via Adamello 16, 20139 Milan, Italy.
Totaro
Maria Grazia
MG
Prosperini
Elena
E
Notarbartolo
Samuele
S
Testa
Giuseppe
G
Natoli
Gioacchino
G
D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003640:Dealkylation; D004790:Enzyme Induction; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056484:Jumonji Domain-Containing Histone Demethylases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013234:Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D014158:Transcription, Genetic; D014161:Transduction, Genetic