title: HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia.
abstract: The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8-Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia.
authors.affiliation: Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, CO 80309, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galbraith
authors.forename: Mary A
authors.initials: MA
authors.lastname: Allen
authors.forename: Claire L
authors.initials: CL
authors.lastname: Bensard
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Wang
authors.forename: Marie K
authors.initials: MK
authors.lastname: Schwinn
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.forename: Henry W
authors.initials: HW
authors.lastname: Long
authors.forename: Danette L
authors.initials: DL
authors.lastname: Daniels
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: Robin D
authors.initials: RD
authors.lastname: Dowell
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Espinosa
mesh_terms: D000107:Acetylation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D056850:Cyclin-Dependent Kinase 8 / Q000737:chemistry / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D056892:Mediator Complex / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism*; D061805:Transcription Elongation, Genetic
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D056892:Mediator Complex; C447612:CDK11a protein, human; D056850:Cyclin-Dependent Kinase 8; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II