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by claude@2026-07, 2026-07-15
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This study structurally and functionally characterized how dual-role regulators Cti6, Ash1, and Ume6 engage the Sin3 deacetylase complex, revealing principles of dynamic assembly and conserved residues essential for transcription factor anchoring.
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by claude@2026-07, 2026-07-15
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The paper studied how chromatin readers and transcription factors assemble with the Sin3 deacetylase complex to coordinate transitions between repressive and activating transcriptional states. Using an integrative structural dynamics approach (cryo-EM, crosslinking mass spectrometry, fragment-resolved interactome mapping, and crystallography), the authors found that Cti6 competes with Ash1 for dynamic recruitment to a shared peripheral module, while Ume6 binds the Sin3 scaffold via a defined minimal interface. High-throughput mutational scanning identified conserved Sin3 residues required for anchoring transcription factors, and the main caveat is that these findings are derived from the structural/functional dissection of this regulatory assembly rather than direct in vivo disease-specific outcomes. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
ABSTRACT Gene expression is governed by dynamic switches between repressive and activating transcriptional states 1,2 . Among the molecules mediating these transitions, chromatin readers and transcription factors play pivotal roles 3,4 . However, how they assemble with regulatory machineries to enable crosstalk between gene repression and activation remains unknown. Here, we use an integrative structural dynamics approach – combining cryo-EM, crosslinking mass spectrometry, fragment-resolved protein interactome mapping and crystallography – to show how the dual-role chromatin reader Cti6 and transcription factors Ash1 and Ume6 engage the Sin3 deacetylase complex, a major regulatory hub in eukaryotes 5 . We find that Cti6 competes with Ash1 to drive its dynamic recruitment to a shared peripheral module, while Ume6 engages the Sin3 scaffold through a defined, minimal interface. Using high-throughput mutational scanning, we reveal deleterious and gain-of-function mutations in Sin3, identifying evolutionarily conserved residues essential for anchoring transcription factors. Together, these results provide structural and functional insights into how dual-role regulators engage the central Sin3 complex, revealing subtle assembly principles that may facilitate crosstalk between gene repression and activation. They also establish an integrative multidisciplinary framework to dissect the dynamics of macromolecular assemblies across biological systems.
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Dynamic engagement of dual-role regulators by the Sin3 complex
ABSTRACT
Gene expression is governed by dynamic switches between repressive and activating transcriptional states1,2. Among the molecules mediating these transitions, chromatin readers and transcription factors play pivotal roles3,4. However, how they assemble with regulatory machineries to enable crosstalk between gene repression and activation remains unknown. Here, we use an integrative structural dynamics approach – combining cryo-EM, crosslinking mass spectrometry, fragment-resolved protein interactome mapping and crystallography – to show how the dual-role chromatin reader Cti6 and transcription factors Ash1 and Ume6 engage the Sin3 deacetylase complex, a major regulatory hub in eukaryotes5. We find that Cti6 competes with Ash1 to drive its dynamic recruitment to a shared peripheral module, while Ume6 engages the Sin3 scaffold through a defined, minimal interface. Using high-throughput mutational scanning, we reveal deleterious and gain-of-function mutations in Sin3, identifying evolutionarily conserved residues essential for anchoring transcription factors. Together, these results provide structural and functional insights into how dual-role regulators engage the central Sin3 complex, revealing subtle assembly principles that may facilitate crosstalk between gene repression and activation. They also establish an integrative multidisciplinary framework to dissect the dynamics of macromolecular assemblies across biological systems.
Competing Interest Statement
The authors have declared no competing interest.
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