The interaction landscape between transcription factors and the nucleosome

Zhu, Fei; Farnung, Lucas; Kaasinen, Eevi; Sahu, Biswajyoti; Yin, Yimeng; Wei, Bei; Dodonova, S.O.; Cramer, Patrick; Taipale, Jussi

doi:10.1101/240598

Cited by 49 publications

(87 citation statements)

References 100 publications

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“…We show that, at least for some PFs, the answer is no. In accordance with earlier studies (Liu and Kraus, 2017;Zhu et al, 2018), our results demonstrate that Sox2's pioneer activity is regulated by both translational and rotational positioning of its cognate motif within the nucleosome. Dyadpositioned sites support prolonged Sox2 binding compared to end-positioned sites.…”

Section: Distinct Nucleosome Targeting Properties Of Pfssupporting

confidence: 92%

“…A recent study showed that the Sox family TFs exhibit preferred binding around the nucleosome dyad region (Zhu et al, 2018). To dissect the single-molecule binding kinetics of Sox2 at the dyad, we placed the Sox2 binding motif at the center of the 601 NPS (nucleotide #72-78) and assembled a nucleosome substrate Nuc S-Dyad (Figure 2A).…”

Section: Sox2 Stably Engages With Binding Sites Near the Nucleosome Dyadmentioning

confidence: 99%

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Nonreciprocal and Conditional Cooperativity Directs the Pioneer Activity of Pluripotency Transcription Factors

Zheng

Zhao

2019

Preprint

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Cooperative binding of transcription factors (TFs) to chromatin orchestrates gene expression programming and cell fate specification. However the biophysical principles of TF cooperativity remain incompletely understood. Here we use single-molecule fluorescence microscopy to study the partnership between Sox2 and Oct4, two core members of the pluripotency gene regulatory network. We find that Sox2's pioneer activity (the ability to target DNA inside nucleosomes) is strongly affected by the translational and rotational positioning of its binding motif, while Oct4 can access nucleosomal sites with equal capacities. Furthermore, the Sox2-Oct4 pair displays nonreciprocal cooperativity, with Oct4 modulating Sox2's binding to the nucleosome but not vice versa. Such cooperativity is conditional upon the composite motif residing at specific nucleosomal locations. These results reveal that pioneer factors possess distinct properties of nucleosome targeting and suggest that the same set of TFs may differentially regulate transcriptional activity in a gene-specific manner on the basis of their motif positioning in the nucleosomal context.

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Section: Distinct Nucleosome Targeting Properties Of Pfssupporting

confidence: 92%

Section: Sox2 Stably Engages With Binding Sites Near the Nucleosome Dyadmentioning

confidence: 99%

Nonreciprocal and Conditional Cooperativity Directs the Pioneer Activity of Pluripotency Transcription Factors

Zheng

Zhao

2019

Preprint

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“…A recent survey of TFnucleosome binding properties was performed for many different classes of TFs revealing how the nucleosome modifies the orientation and position of the TF binding compared to free DNA. Moreover, many TFs analyzed were capable of inducing nucleosome dissociation upon binding 11 . In the case of Oct4, the canonical configuration known from the structures of Oct4 bound to free DNA 6 is incompatible with nucleosome binding because it involves binding of the POUS and POUHD on opposite sides of DNA.…”

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confidence: 99%

Nucleosomal DNA dynamics mediate Oct4 pioneer factor binding

Huertas

MacCarthy

Schoeler

et al. 2019

Preprint

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Transcription factor (TF) proteins bind to DNA to regulate gene expression. Normally, accessibility to DNA is required for their function. However, in the nucleus the DNA is often inaccessible, wrapped around histone proteins in nucleosomes forming the chromatin.Pioneer TFs are thought to induce chromatin opening by recognizing their DNA binding sites on nucleosomes. For example, Oct4, a master regulator and inducer of stem cell pluripotency, binds to DNA in nucleosomes in a sequence specific manner. Here we reveal the structural dynamics of nucleosomes that mediate Oct4 binding. Nucleosome mobility and the amplitude of nucleosome motions such as breathing and twisting correlate with the number of Oct4 binding sites available. Moreover, the regions around the binding sites display higher local mobility. Probing different structures of Oct4-nucleosome complexes, we show that alternative configurations display stable protein-DNA interactions and are compatible with the DNA curvature and DNA-histone interactions.

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“…For most transcription factors nucleosome wrapping substantially inhibits association with DNA both by inhibiting association and enhancing dissociation [56,57]. However, for others, binding to nucleosomes is as efficient as naked DNA, and some even prefer nucleosomal DNA [58,59]. It is not fully clear how this is achieved mechanistically but it has recently been shown that this is due to decreased dissociation rates [60] and for some may include stabilizing contacts with the histones [61].…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis of Specific DNA Binding by the BRG1 AT-hook and Bromodomain

Sanchez

Zhang

Evoli

et al. 2019

Preprint

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AbstractThe ATP-dependent BAF chromatin remodeling complex plays a critical role in gene regulation by modulating chromatin architecture, and is frequently mutated in cancer. Indeed, subunits of the BAF complex are found to be mutated in >20% of human tumors. The mechanism by which BAF properly navigates chromatin is not fully understood, but is thought to involve a multivalent network of histone and DNA contacts. We previously identified a composite domain in the BRG1 ATPase subunit that is capable of associating with both histones and DNA in a multivalent manner. Mapping the DNA binding pocket revealed that it contains several cancer mutations. Here, we utilize SELEX-seq to identify the DNA specificity of this composite domain and NMR spectroscopy and molecular modelling to determine the structural basis of DNA binding. Finally, we demonstrate that cancer mutations in this domain alter the mode of DNA association.

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The interaction landscape between transcription factors and the nucleosome

Abstract: 16Nucleosomes cover most of the genome and are thought to be displaced by

Cited by 49 publications

References 100 publications

Nonreciprocal and Conditional Cooperativity Directs the Pioneer Activity of Pluripotency Transcription Factors

Nonreciprocal and Conditional Cooperativity Directs the Pioneer Activity of Pluripotency Transcription Factors

Nucleosomal DNA dynamics mediate Oct4 pioneer factor binding

The Molecular Basis of Specific DNA Binding by the BRG1 AT-hook and Bromodomain

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