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Quantitative models for accelerated protein dissociation from nucleosomal DNA.

Chen C, Bundschuh R - Nucleic Acids Res. (2014)

Bottom Line: This reduces the rate of transcription factor binding and is a known mechanism for regulation of gene expression via chromatin structure.There are two possible explanations for such an increase in off-rate short of an active role of the nucleosome in pushing the transcription factor off the DNA: (i) for dimeric transcription factors the nucleosome can change the equilibrium between monomeric and dimeric binding or (ii) the nucleosome can change the equilibrium between specific and non-specific binding to the DNA.We explicitly model both scenarios and find that dimeric binding can explain a large increase in off-rate while the non-specific binding model cannot be reconciled with the large, experimentally observed increase.

View Article: PubMed Central - PubMed

Affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA Center for RNA Biology, The Ohio State University, Columbus, OH, USA.

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Dimeric model of TF dissociation from (A) a nucleosome and (B) from naked DNA. (A) In the presence of a nucleosome (yellow cylinder), if the site which is closer to the nucleosome dyad dissociates first (State I to State II), the nucleosome can rewrap (State II to State V). Once the other site dissociates, the TF will fall off (State V to State VI) and the nucleosome will be completely wrapped (State VI to State VII). If the further site dissociates first (State I to State III), the nucleosome needs to wait for the closer site to dissociate and then be rewrapped (State III to VII). The dark blue line is the DNA that is wrapped around the histone core while the light green line is the DNA unwrapped from the nucleosome. The red dashed line is the TF binding site. (B) In the absence of the nucleosome, when one of two binding sites dissociates (State I to State II or III), it can rebind again (State II or III to State I) or completely dissociate (State II or III to State IV).
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Figure 1: Dimeric model of TF dissociation from (A) a nucleosome and (B) from naked DNA. (A) In the presence of a nucleosome (yellow cylinder), if the site which is closer to the nucleosome dyad dissociates first (State I to State II), the nucleosome can rewrap (State II to State V). Once the other site dissociates, the TF will fall off (State V to State VI) and the nucleosome will be completely wrapped (State VI to State VII). If the further site dissociates first (State I to State III), the nucleosome needs to wait for the closer site to dissociate and then be rewrapped (State III to VII). The dark blue line is the DNA that is wrapped around the histone core while the light green line is the DNA unwrapped from the nucleosome. The red dashed line is the TF binding site. (B) In the absence of the nucleosome, when one of two binding sites dissociates (State I to State II or III), it can rebind again (State II or III to State I) or completely dissociate (State II or III to State IV).

Mentions: In the study of Luo et al. (12), two transcription factors were investigated: (i) Escherichia coli transcription repressor protein LexA, which has a very specific binding site of 16 bp and dissociation constant of Kd ∼ 0.1 nM (17), and forms a stable dimer where each monomer binds to a half site of the whole LexA binding site (13,18,19); (ii) A model eukaryotic transcription factor Gal4, which recognizes its 17 bp consensus binding site with an even smaller dissociation constant of Kd ∼ 10 pM (20) and also binds DNA as a homodimer (20,21). Since both TFs are homodimers and bind to two specific half sites, we propose that one of the two binding sites will dissociate first. In the presence of a nucleosome (Figure 1A), if the site that is closer to the nucleosome dyad dissociates first, the nucleosome can rewrap and prevent rebinding. Once the other site dissociates, the TF will completely detach. Therefore, when the nucleosome is present it can ‘rachet’ the protein off by blocking reassociation at the site proximal to it. However, in the absence of the nucleosome, when one of two binding sites dissociates, it would rapidly rebind again, meaning that both sites dissociating at once would be rare. This should increase the off-rate of the TF in the presence of a nucleosome relative to naked DNA, just as it does in the presence of multiple dimeric non-specific binding proteins saturating on a stretch of DNA (15).


Quantitative models for accelerated protein dissociation from nucleosomal DNA.

Chen C, Bundschuh R - Nucleic Acids Res. (2014)

Dimeric model of TF dissociation from (A) a nucleosome and (B) from naked DNA. (A) In the presence of a nucleosome (yellow cylinder), if the site which is closer to the nucleosome dyad dissociates first (State I to State II), the nucleosome can rewrap (State II to State V). Once the other site dissociates, the TF will fall off (State V to State VI) and the nucleosome will be completely wrapped (State VI to State VII). If the further site dissociates first (State I to State III), the nucleosome needs to wait for the closer site to dissociate and then be rewrapped (State III to VII). The dark blue line is the DNA that is wrapped around the histone core while the light green line is the DNA unwrapped from the nucleosome. The red dashed line is the TF binding site. (B) In the absence of the nucleosome, when one of two binding sites dissociates (State I to State II or III), it can rebind again (State II or III to State I) or completely dissociate (State II or III to State IV).
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Figure 1: Dimeric model of TF dissociation from (A) a nucleosome and (B) from naked DNA. (A) In the presence of a nucleosome (yellow cylinder), if the site which is closer to the nucleosome dyad dissociates first (State I to State II), the nucleosome can rewrap (State II to State V). Once the other site dissociates, the TF will fall off (State V to State VI) and the nucleosome will be completely wrapped (State VI to State VII). If the further site dissociates first (State I to State III), the nucleosome needs to wait for the closer site to dissociate and then be rewrapped (State III to VII). The dark blue line is the DNA that is wrapped around the histone core while the light green line is the DNA unwrapped from the nucleosome. The red dashed line is the TF binding site. (B) In the absence of the nucleosome, when one of two binding sites dissociates (State I to State II or III), it can rebind again (State II or III to State I) or completely dissociate (State II or III to State IV).
Mentions: In the study of Luo et al. (12), two transcription factors were investigated: (i) Escherichia coli transcription repressor protein LexA, which has a very specific binding site of 16 bp and dissociation constant of Kd ∼ 0.1 nM (17), and forms a stable dimer where each monomer binds to a half site of the whole LexA binding site (13,18,19); (ii) A model eukaryotic transcription factor Gal4, which recognizes its 17 bp consensus binding site with an even smaller dissociation constant of Kd ∼ 10 pM (20) and also binds DNA as a homodimer (20,21). Since both TFs are homodimers and bind to two specific half sites, we propose that one of the two binding sites will dissociate first. In the presence of a nucleosome (Figure 1A), if the site that is closer to the nucleosome dyad dissociates first, the nucleosome can rewrap and prevent rebinding. Once the other site dissociates, the TF will completely detach. Therefore, when the nucleosome is present it can ‘rachet’ the protein off by blocking reassociation at the site proximal to it. However, in the absence of the nucleosome, when one of two binding sites dissociates, it would rapidly rebind again, meaning that both sites dissociating at once would be rare. This should increase the off-rate of the TF in the presence of a nucleosome relative to naked DNA, just as it does in the presence of multiple dimeric non-specific binding proteins saturating on a stretch of DNA (15).

Bottom Line: This reduces the rate of transcription factor binding and is a known mechanism for regulation of gene expression via chromatin structure.There are two possible explanations for such an increase in off-rate short of an active role of the nucleosome in pushing the transcription factor off the DNA: (i) for dimeric transcription factors the nucleosome can change the equilibrium between monomeric and dimeric binding or (ii) the nucleosome can change the equilibrium between specific and non-specific binding to the DNA.We explicitly model both scenarios and find that dimeric binding can explain a large increase in off-rate while the non-specific binding model cannot be reconciled with the large, experimentally observed increase.

View Article: PubMed Central - PubMed

Affiliation: Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA Center for RNA Biology, The Ohio State University, Columbus, OH, USA.

Show MeSH
Related in: MedlinePlus