title: Perturbations of PIP3 signalling trigger a global remodelling of mRNA landscape and reveal a transcriptional feedback loop.
abstract: PIP3 is synthesized by the Class I PI3Ks and regulates complex cell responses, such as growth and migration. Signals that drive long-term reshaping of cell phenotypes are difficult to resolve because of complex feedback networks that operate over extended times. PIP3-dependent modulation of mRNA accumulation is clearly important in this process but is poorly understood. We have quantified the genome-wide mRNA-landscape of non-transformed, breast epithelium-derived MCF10a cells and its response to acute regulation by EGF, in the presence or absence of a PI3Kα inhibitor, compare it to chronic activation of PI3K signalling by cancer-relevant mutations (isogenic cells expressing an oncomutant PI3Kα allele or lacking the PIP3-phosphatase/tumour-suppressor, PTEN). Our results show that whilst many mRNAs are changed by long-term genetic perturbation of PIP3 signalling ('butterfly effect'), a much smaller number do so in a coherent fashion with the different PIP3 perturbations. This suggests a subset of more directly regulated mRNAs. We show that mRNAs respond differently to given aspects of PIP3 regulation. Some PIP3-sensitive mRNAs encode PI3K pathway components, thus suggesting a transcriptional feedback loop. We identify the transcription factor binding motifs SRF and PRDM1 as important regulators of PIP3-sensitive mRNAs involved in cell movement.
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Vladimir Yu
authors.initials: VY
authors.lastname: Kiselev
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Juvin
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Mouhannad
authors.initials: M
authors.lastname: Malek
authors.affiliation: London Research Institute, London, WC2A 3LY, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Luscombe
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Phillip
authors.initials: P
authors.lastname: Hawkins
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK EMBL-European Bioinformatics Institute, Hinxton, CB10 1SD, UK lenov@babraham.ac.uk.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Le Novère
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
mesh_terms: D001940:Breast / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D059372:Nucleotide Motifs; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018129:Phosphatidylinositol Phosphates; D012333:RNA, Messenger; D014157:Transcription Factors; C060974:phosphatidylinositol 3,4,5-triphosphate; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human