Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors.
Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown. Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals. This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression. These events link an inhibitory methylation component of the histone code to a broadly used strategy that circumvents pathological constitutive gene induction by physiologically regulated transcription factors.
Garcia-Bassets
Ivan
I
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Kwon
Young-Soo
YS
Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Telese
Francesca
F
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Prefontaine
Gratien G
GG
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Hutt
Kasey R
KR
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Cheng
Christine S
CS
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Ju
Bong-Gun
BG
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Ohgi
Kenneth A
KA
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Wang
Jianxun
J
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Escoubet-Lozach
Laure
L
Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Rose
David W
DW
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Glass
Christopher K
CK
Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Fu
Xiang-Dong
XD
Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
Rosenfeld
Michael G
MG
Howard Hughes Medical Institute, Department of Molecular Medicine, University of California, San Diego, School of Medicine 9500 Gilman Drive, La Jolla, CA 92093-0648.
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D042421:Histone Code; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D006657:Histones; D008024:Ligands; D004958:Estradiol; D056466:Histone Demethylases; C495195:KDM1A protein, human; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase