title: PITX1, a specificity determinant in the HIF-1α-mediated transcriptional response to hypoxia.
abstract: Hypoxia is an important developmental cue for multicellular organisms but it is also a contributing factor for several human pathologies, such as stroke, cardiovascular diseases and cancer. In cells, hypoxia activates a major transcriptional program coordinated by the Hypoxia Inducible Factor (HIF) family. HIF can activate more than one hundred targets but not all of them are activated at the same time, and there is considerable cell type variability. In this report we identified the paired-like homeodomain pituitary transcription factor (PITX1), as a transcription factor that helps promote specificity in HIF-1α dependent target gene activation. Mechanistically, PITX1 associates with HIF-1β and it is important for the induction of certain HIF-1 dependent genes but not all. In particular, PITX1 controls the HIF-1α-dependent expression of the histone demethylases; JMJD2B, JMJD2A, JMJD2C and JMJD1B. Functionally, PITX1 is required for the survival and proliferation responses in hypoxia, as PITX1 depleted cells have higher levels of apoptotic markers and reduced proliferation. Overall, our study identified PITX1 as a key specificity factor in HIF-1α dependent responses, suggesting PITX1 as a protein to target in hypoxic cancers.
authors.affiliation: a Centre for Gene Regulation and Expression; College of Life Sciences ; University of Dundee ; Dundee , UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.forename: Daniel
authors.initials: D
authors.lastname: Bandarra
authors.forename: Michael
authors.initials: M
authors.lastname: Batie
authors.forename: John
authors.initials: J
authors.lastname: Biddlestone
authors.forename: Sonia
authors.initials: S
authors.lastname: Moniz
authors.forename: Brian
authors.initials: B
authors.lastname: Ortmann
authors.forename: Alena
authors.initials: A
authors.lastname: Shmakova
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D038761:Photobleaching; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497396:ARNT protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C101485:homeobox protein PITX1; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D056466:Histone Demethylases
keywords: ChIP; HIF; HIF-1β; Histone methylation; JMJC; JMJD2B; PITX1; hypoxia; transcription