title: Interactions between Notch- and hypoxia-induced transcriptomes in embryonic stem cells.
abstract: Interaction between key signaling mechanisms is important to generate the diversity in signaling output required for proper control of cellular differentiation and function, although the molecular manifestations of such cross-talk are only partially understood. Notch signaling and the cellular response to hypoxia intersect at different points in the signaling cascades, and in this report we analyze the consequences of this cross-talk at the transcriptome level. Mouse ES cells were subjected to various combinations of hypoxia and/or activated Notch signaling, and the transcriptome changes could be grouped into different categories, reflecting various modes of hypoxia and Notch signaling integration. Two principal categories of novel Notch- and hypoxia-induced genes were identified: (i) a larger set of Notch or hypoxic target genes which were induced by one pathway and not significantly affected by the activity status of the other pathway and (ii) a smaller set of genes co-regulated by Notch and hypoxia. In the latter category, we identified genes that were induced by hypoxia and the expression of which was enhanced by active Notch signaling and another group of genes that were induced by Notch and hypoxia independently. Several of the hypoxia- and Notch-induced genes were found to be upregulated in various forms of cancer. Identification of genes co-regulated by the two pathways may provide a molecular platform to better understand the intersection between the two signaling cascades in normal development and cancer.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Heather
authors.initials: H
authors.lastname: Main
authors.forename: Kian Leong
authors.initials: KL
authors.lastname: Lee
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Saija
authors.initials: S
authors.lastname: Haapa-Paananen
authors.forename: Henrik
authors.initials: H
authors.lastname: Edgren
authors.forename: Shaobo
authors.initials: S
authors.lastname: Jin
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D051880:Receptors, Notch