2020
DOI: 10.1016/j.molcel.2020.01.027
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Context-Dependent Gene Regulation by Homeodomain Transcription Factor Complexes Revealed by Shape-Readout Deficient Proteins

Abstract: Highlights d DNA shape readout by homeodomain TF complexes is revealed using SELEX-seq assays d A shape readout-impaired homeodomain mutant destabilizes specific TF complexes d This mutant was exploited to map TF complex composition and function genome wide d The same mutation in an orthologous homeodomain is associated with a human disease

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Cited by 32 publications
(25 citation statements)
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References 88 publications
(112 reference statements)
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“…The resulting model revealed significant cooperativity (ΔΔ G config ≈ 2 RT ) when Hth binds 8-13 bps upstream of Exd:Ubx (Figure 3b), which, along with our monomer and heterodimer models, mirrored our previous results 22, 34 . While a larger spacing is tolerated when Hth is reversed, cooperativity is lost when Hth binds far away from the Exd:Ubx half-site, regardless of orientation.…”
Section: Resultssupporting
confidence: 87%
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“…The resulting model revealed significant cooperativity (ΔΔ G config ≈ 2 RT ) when Hth binds 8-13 bps upstream of Exd:Ubx (Figure 3b), which, along with our monomer and heterodimer models, mirrored our previous results 22, 34 . While a larger spacing is tolerated when Hth is reversed, cooperativity is lost when Hth binds far away from the Exd:Ubx half-site, regardless of orientation.…”
Section: Resultssupporting
confidence: 87%
“…We first focused on co-factors, which modulate TF binding in a cell-type-specific manner. Despite the growing number of SELEX assays characterizing TF complexes 9,11,34 , it remains a challenge to quantify sequence recognition in a way that clearly separates the contributions from many potential TF complexes and their various internal structural configurations – a problem that grows exponentially with the number of factors assayed. In a novel approach that builds upon our multi-experiment framework, we measure subunit binding specificity and cooperativity by explicitly modeling the allowed complexes in multiple SELEX datasets that probe different TF combinations.…”
Section: Resultsmentioning
confidence: 99%
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“…4b). Finally, the analysis of Hth Chip-seq data performed in the wing imaginal discs 20,21 revealed a significant binding on the P1 cis-regulatory region and another putative enhancer of Antp (Fig. 4c).…”
Section: Resultsmentioning
confidence: 90%
“…For example, yeast bHLH TFs Cbf1 and Tye7 bind DNA targets with differential preference for the genomic regions flanking E-Box sites according to DNA shape of binding sites [6]. Another example is Homeodomain TFs Hox-Exd-Hth trimer which prefers DNA sequences with a complex DNA shape that includes optimally spaced minor groove width minima [7]. In the last decade, sequence-based high-throughput technologies to measure protein DNA-binding specificities have revolutionized our ability to measure TF-DNA specificity.…”
Section: Introductionmentioning
confidence: 99%