title: A high-resolution gene expression atlas of epistasis between gene-specific transcription factors exposes potential mechanisms for genetic interactions.
abstract: BACKGROUND
  Genetic interactions, or non-additive effects between genes, play a crucial role in many cellular processes and disease. Which mechanisms underlie these genetic interactions has hardly been characterized. Understanding the molecular basis of genetic interactions is crucial in deciphering pathway organization and understanding the relationship between genotype, phenotype and disease.
  
  
  RESULTS
  To investigate the nature of genetic interactions between gene-specific transcription factors (GSTFs) in Saccharomyces cerevisiae, we systematically analyzed 72 GSTF pairs by gene expression profiling double and single deletion mutants. These pairs were selected through previously published growth-based genetic interactions as well as through similarity in DNA binding properties. The result is a high-resolution atlas of gene expression-based genetic interactions that provides systems-level insight into GSTF epistasis. The atlas confirms known genetic interactions and exposes new ones. Importantly, the data can be used to investigate mechanisms that underlie individual genetic interactions. Two molecular mechanisms are proposed, "buffering by induced dependency" and "alleviation by derepression".
  
  
  CONCLUSIONS
  These mechanisms indicate how negative genetic interactions can occur between seemingly unrelated parallel pathways and how positive genetic interactions can indirectly expose parallel rather than same-pathway relationships. The focus on GSTFs is important for understanding the transcription regulatory network of yeast as it uncovers details behind many redundancy relationships, some of which are completely new. In addition, the study provides general insight into the complex nature of epistasis and proposes mechanistic models for genetic interactions, the majority of which do not fall into easily recognizable within- or between-pathway relationships.
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Katrin
authors.initials: K
authors.lastname: Sameith
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Saman
authors.initials: S
authors.lastname: Amini
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Marian J A
authors.initials: MJ
authors.lastname: Groot Koerkamp
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Dik
authors.initials: D
authors.lastname: van Leenen
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Mariel
authors.initials: M
authors.lastname: Brok
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brabers
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Lijnzaad
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Sander R
authors.initials: SR
authors.lastname: van Hooff
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Joris J
authors.initials: JJ
authors.lastname: Benschop
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Tineke L
authors.initials: TL
authors.lastname: Lenstra
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Apweiler
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Sake
authors.initials: S
authors.lastname: van Wageningen
authors.affiliation: Theoretical Biology and Bioinformatics, Department of Biology, Utrecht University, Padualaan 8, Utrecht, The Netherlands.
authors.forename: Berend
authors.initials: B
authors.lastname: Snel
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.affiliation: Molecular Cancer Research, University Medical Centre Utrecht, Universiteitsweg 100, Utrecht, The Netherlands. p.kemmeren@umcutrecht.nl.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kemmeren
mesh_terms: D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015723:Gene Library; D063990:Gene Ontology; D058977:Molecular Sequence Annotation; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors