Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex.
Timely acquisition of cell fates and the elaborate control of growth in numerous organs depend on Notch signaling. Upon ligand binding, the core transcription factor RBP-J activates transcription of Notch target genes. In the absence of signaling, RBP-J switches off target gene expression, assuring the tight spatiotemporal control of the response by a mechanism incompletely understood. Here we show that the histone demethylase KDM5A is an integral, conserved component of Notch/RBP-J gene silencing. Methylation of histone H3 Lys 4 is dynamically erased and re-established at RBP-J sites upon inhibition and reactivation of Notch signaling. KDM5A interacts physically with RBP-J; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses.
Liefke
Robert
R
Max-Planck-Institute of Immunobiology, Freiburg, Germany.
Oswald
Franz
F
Alvarado
Cristobal
C
Ferres-Marco
Dolores
D
Mittler
Gerhard
G
Rodriguez
Patrick
P
Dominguez
Maria
M
Borggrefe
Tilman
T
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster; D006657:Histones / Q000378:metabolism; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism*; D056485:Retinoblastoma-Binding Protein 2 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse; D056485:Retinoblastoma-Binding Protein 2; C104035:Dtx1 protein, mouse; D044767:Ubiquitin-Protein Ligases