The TIP60 Complex Is a Conserved Coactivator of HIF1A.
Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. Despite their established roles in normal physiology and numerous pathologies, the molecular mechanisms by which they control gene expression remain poorly understood. We report here a conserved role for the TIP60 complex as a HIF1 transcriptional cofactor in Drosophila and human cells. TIP60 (KAT5) is required for HIF1-dependent gene expression in fly cells and embryos and colorectal cancer cells. HIF1A interacts with and recruits TIP60 to chromatin. TIP60 is dispensable for HIF1A association with its target genes but is required for HIF1A-dependent chromatin modification and RNA polymerase II activation in hypoxia. In human cells, global analysis of HIF1A-dependent gene activity reveals that most HIF1A targets require either TIP60, the CDK8-Mediator complex, or both as coactivators for full expression in hypoxia. Thus, HIF1A employs functionally diverse cofactors to regulate different subsets of genes within its transcriptional program.
Instituto Leloir, 1405 Buenos Aires, Argentina.
Joel I
JI
Perez-Perri
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
Veronica L
VL
Dengler
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
K Audrey
KA
Audetat
Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA.
Ahwan
A
Pandey
Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Elizabeth A
EA
Bonner
Promega Corporation, Madison, WI 53711, USA.
Marjeta
M
Urh
Promega Corporation, Madison, WI 53711, USA.
Jacqui
J
Mendez
Promega Corporation, Madison, WI 53711, USA.
Danette L
DL
Daniels
Instituto Leloir, 1405 Buenos Aires, Argentina.
Pablo
P
Wappner
Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: matthew.galbraith@ucdenver.edu.
Matthew D
MD
Galbraith
Linda Crnic Institute for Down Syndrome, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA. Electronic address: joaquin.espinosa@ucdenver.edu.
Joaquín M
JM
Espinosa
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D017124:Conserved Sequence; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5 / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D002843:Chromatin; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D021122:Protein Subunits; C100429:Sima protein, Drosophila; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C511056:Tip60 protein, Drosophila; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D012319:RNA Polymerase II