Probing Allostery Through DNA

Kim, Sang-Jin; Bröstromer, Erik; Xing, Dong; Jin, Jianshi; Chong, Shasha; Ge, Hao; Wang, Siyuan; Gu, Chan; Yang, Lijiang; Gao, Yi Qin; Su, Xiao Dong; Sun, Yujie; Xie, Xiao

doi:10.1126/science.1229223

Cited by 256 publications

(311 citation statements)

References 70 publications

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“…Allosteric modulation of DNA may provide one explanation for this observation. Transcription factors such as glucocorticoid receptor were recently reported to modulate DNA allosterically to facilitate binding by another DNAbinding protein that does not appear to make protein-protein contacts (52). Furthermore, we have previously shown that a polyamide, lacking a domain to interact with a protein partner, facilitates the binding of a transcription factor to an adjacent site by 10-fold (53).…”

Section: Discussionmentioning

confidence: 99%

Synthetic genome readers target clustered binding sites across diverse chromatin states

Erwin

Grieshop

Bhimsaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Targeting the genome with sequence-specific DNA-binding molecules is a major goal at the interface of chemistry, biology, and precision medicine. Polyamides, composed of N-methylpyrrole and N-methylimidazole monomers, are a class of synthetic molecules that can be rationally designed to “read” specific DNA sequences. However, the impact of different chromatin states on polyamide binding in live cells remains an unresolved question that impedes their deployment in vivo. Here, we use cross-linking of small molecules to isolate chromatin coupled to sequencing to map the binding of two bioactive and structurally distinct polyamides to genomes directly within live H1 human embryonic stem cells. This genome-wide view from live cells reveals that polyamide-based synthetic genome readers bind cognate sites that span a range of binding affinities. Polyamides can access cognate sites within repressive heterochromatin. The occupancy patterns suggest that polyamides could be harnessed to target loci within regions of the genome that are inaccessible to other DNA-targeting molecules.

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Section: Discussionmentioning

confidence: 99%

Synthetic genome readers target clustered binding sites across diverse chromatin states

Erwin

Grieshop

Bhimsaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This is typically the case when the DNA deformation anticipates the DNA structure in the complex formed by the binding site and its ligand. And pertinent to eukaryotic gene expression, closely positioned nucleosomes have been shown quite recently to modify the binding affinity of a transcription factor to a response element inserted in a neighboring linker DNA [31]. Note that speaking of DNA deformation implicitly refers to a lock-and-key mechanism, which may not be the case: an alternative view is a shift of an equilibrium between two pre-existing DNA conformations upon the first binding event (conformational capture).…”

Section: Protein-binding Event May Trigger Dna Allosteric Transitionsmentioning

confidence: 99%

Chromatin fiber allostery and the epigenetic code

Lesne

Foray

Cathala

et al. 2015

J. Phys.: Condens. Matter

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Abstract. The notion of allostery introduced for proteins about fifty years ago has been extended since then to DNA allostery, where a locally triggered DNA structural transition remotely controls other DNA-binding events. We further extend this notion and propose that chromatin fiber allosteric transitions, induced by histone-tail covalent modifications, may play a key role in transcriptional regulation. We present an integrated scenario articulating allosteric mechanisms at different scales: allosteric transitions of the condensed chromatin fiber induced by histone-tail acetylation modify the mechanical constraints experienced by the embedded DNA, thus possibly controlling DNA-binding of allosteric transcription factors or further allosteric mechanisms at the linker DNA level. At a higher scale, different epigenetic constraints delineate different statistically dominant subsets of accessible chromatin fiber conformations, which each favors the assembly of dedicated regulatory complexes, as detailed on the emblematic example of the mouse Igf2-H19 gene locus and its parental imprinting. This physical view offers a mechanistic and spatially structured explanation of the observed correlation between transcriptional activity and histone modifications. The evolutionary origin of allosteric control supports to speak of an "epigenetic code", by which events involved in transcriptional regulation are encoded in histone modifications in a context-dependent way.

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“…The impact of DNA polymorphism in DNA allosterism [64] has been also the subject of the work of several groups [62,65], while others centered their efforts in understanding the origin of DNA curvature [66]. Minicircles, a specially curved form of DNA traditionally challenging for the field due to the high mechanical tension that they can incorporate, have been recently revisited by different authors who explored the origins of superhelicity and the limits of the elastic response of DNA to distortion [66,67].…”

Section: Atomistic Studiesmentioning

confidence: 99%

Multiscale simulation of DNA

Dans¹,

Walther

Gómez

et al. 2016

Current Opinion in Structural Biology

135

130

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DNA is not only among the most important molecules in life, but a meeting point for biology, physics and chemistry, being studied by numerous techniques. Theoretical methods can help in gaining a detailed understanding of DNA structure and function, but their practical use is hampered by the multiscale nature of this molecule. In this regard, the study of DNA covers a broad range of different topics, from sub-Angstrom details of the electronic distributions of nucleobases, to the mechanical properties of millimeter-long chromatin fibers. Some of the biological processes involving DNA occur in femtoseconds, while others require years. In this review, we describe the most recent theoretical methods that have been considered to study DNA, from the electron to the chromosome, enriching our knowledge on this fascinating molecule.

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Probing Allostery Through DNA

Cited by 256 publications

References 70 publications

Synthetic genome readers target clustered binding sites across diverse chromatin states

Synthetic genome readers target clustered binding sites across diverse chromatin states

Chromatin fiber allostery and the epigenetic code

Multiscale simulation of DNA

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