title: High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions.
abstract: Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Fas1p and Ole1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global two-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland. Electronic address: dominic.hoepfner@novartis.com.
authors.forename: Dominic
authors.initials: D
authors.lastname: Hoepfner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Helliwell
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Heather
authors.initials: H
authors.lastname: Sadlish
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Schuierer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Ireos
authors.initials: I
authors.lastname: Filipuzzi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brachat
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bhullar
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Uwe
authors.initials: U
authors.lastname: Plikat
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Abraham
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Altorfer
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Aust
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Baeriswyl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Cerino
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Lena
authors.initials: L
authors.lastname: Chang
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Estoppey
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Juerg
authors.initials: J
authors.lastname: Eichenberger
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Frederiksen
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Annika
authors.initials: A
authors.lastname: Hohendahl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Melin
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Nigsch
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Oakeley
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Petitjean
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Petersen
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Riedl
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Staedtler
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Studer
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wetzel
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Fishman
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
authors.forename: N Rao
authors.initials: NR
authors.lastname: Movva
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D053898:Biosynthetic Pathways; D025141:Drug Resistance, Fungal; D015966:Gene Expression Regulation, Fungal; D057166:High-Throughput Screening Assays; D008969:Molecular Sequence Data; D010802:Phylogeny; D012441:Saccharomyces cerevisiae / Q000737:chemistry* / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D029701:Saccharomyces cerevisiae Proteins
keywords: Chemogenomic profiling; Cmpd; FAS; HIP; HIP HOP profiling; HOP; Mechanism of action; MoA; Target identification; Yeast; compound; fatty acid synthase; haploinsufficiency profiling; homozygous profiling; mechanism of action