title: Deciphering the Sox-Oct partner code by quantitative cooperativity measurements.
abstract: Several Sox-Oct transcription factor (TF) combinations have been shown to cooperate on diverse enhancers to determine cell fates. Here, we developed a method to quantify biochemically the Sox-Oct cooperation and assessed the pairing of the high-mobility group (HMG) domains of 11 Sox TFs with Oct4 on a series of composite DNA elements. This way, we clustered Sox proteins according to their dimerization preferences illustrating that Sox HMG domains evolved different propensities to cooperate with Oct4. Sox2, Sox14, Sox21 and Sox15 strongly cooperate on the canonical element but compete with Oct4 on a recently discovered compressed element. Sry also cooperates on the canonical element but binds additively to the compressed element. In contrast, Sox17 and Sox4 cooperate more strongly on the compressed than on the canonical element. Sox5 and Sox18 show some cooperation on both elements, whereas Sox8 and Sox9 compete on both elements. Testing rationally mutated Sox proteins combined with structural modeling highlights critical amino acids for differential Sox-Oct4 partnerships and demonstrates that the cooperativity correlates with the efficiency in producing induced pluripotent stem cells. Our results suggest selective Sox-Oct partnerships in genome regulation and provide a toolset to study protein cooperation on DNA.
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
authors.forename: Calista K L
authors.initials: CK
authors.lastname: Ng
authors.forename: Noel X
authors.initials: NX
authors.lastname: Li
authors.forename: Sheena
authors.initials: S
authors.lastname: Chee
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Prasanna R
authors.initials: PR
authors.lastname: Kolatkar
authors.forename: Ralf
authors.initials: R
authors.lastname: Jauch
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055747:SOX Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D050814:Octamer Transcription Factor-3; D055747:SOX Transcription Factors; D004247:DNA