Sequence-Specificity and Energy Landscapes of DNA-Binding Molecules

Tietjen, Joshua R.; Donato, Leslie J.; Bhimisaria, Devesh; Ansari, Aseem Z.

doi:10.1016/b978-0-12-385075-1.00001-9

Cited by 24 publications

(45 citation statements)

References 64 publications

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“…2A). CSI analysis was performed on binding data derived from either high-density DNA microarrays or massively parallel NGS (20)(21)(22) (Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…Remarkably, rationally designed polyamides fed to Drosophila larvae induced classic homeotic patterns of developmental reprogramming (19). To understand the rules that govern polyamide function, several groups have independently examined the DNA sequence specificity of this class of molecules in vitro (20)(21)(22)(23)(24)(25). In particular, we developed cognate site identifier (CSI) analysis to interrogate DNA sequence specificity and affinity comprehensively for any given sequence across half a million permutations of a 10-mer binding site (20,21).…”

mentioning

confidence: 99%

“…In particular, we developed cognate site identifier (CSI) analysis to interrogate DNA sequence specificity and affinity comprehensively for any given sequence across half a million permutations of a 10-mer binding site (20,21). CSI studies demonstrated that affinities and specificities of polyamides for their cognate sites rival the affinities and specificities of natural transcription factors (20)(21)(22)(23). Moreover, CSI data yielded polyamide affinity measurements for every 10-mer sequence that occurs in any given genome (21).…”

mentioning

confidence: 99%

“…Moreover, CSI data yielded polyamide affinity measurements for every 10-mer sequence that occurs in any given genome (21). Applying this information to map binding potential across the genome led to CSI-based "genomescapes" that predict thousands of putative polyamide-binding sites of varying affinities across the human genome (21,22).…”

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confidence: 99%

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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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“…2A). CSI analysis was performed on binding data derived from either high-density DNA microarrays or massively parallel NGS (20)(21)(22) (Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…[25][26][27][28][29] Sequence specificities of Py-Im polyamides have also been investigated by using high-throughput sequencing. [30][31][32] Here, we designed and synthesized thirteen Py-Im polyamides ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Sequence-specific DNA binding by long hairpin pyrrole–imidazole polyamides containing an 8-amino-3,6-dioxaoctanoic acid unit

Sawatani

Kashiwazaki

Chandran

et al. 2016

Bioorganic & Medicinal Chemistry

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Mapping Polyamide–DNA Interactions in Human Cells Reveals a New Design Strategy for Effective Targeting of Genomic Sites

et al. 2014

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Targeting the genome with sequence-specific synthetic molecules is a major goal at the interface of chemistry, biology, and personalized medicine. Pyrrole/imidazole based polyamides can be rationally designed to target specific DNA sequences with exquisite precision in vitro; yet, the biological outcomes are often difficult to interpret using current models of binding energetics. To directly identify the binding sites of polyamides across the genome, we designed, synthesized, and tested polyamide derivatives that enabled covalent crosslinking and localization of polyamide–DNA interaction sites in live human cells. Bioinformatic analysis of the data reveals that clustered binding sites, spanning a broad range of affinities, best predict occupancy in cells. In contrast to the prevailing paradigm of targeting single high-affinity sites, our results point to a new design principle to deploy polyamides and perhaps other synthetic molecules to effectively target desired genomic sites in vivo.

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Sequence-Specificity and Energy Landscapes of DNA-Binding Molecules

Cited by 24 publications

References 64 publications

Synthetic genome readers target clustered binding sites across diverse chromatin states

Synthetic genome readers target clustered binding sites across diverse chromatin states

Sequence-specific DNA binding by long hairpin pyrrole–imidazole polyamides containing an 8-amino-3,6-dioxaoctanoic acid unit

Mapping Polyamide–DNA Interactions in Human Cells Reveals a New Design Strategy for Effective Targeting of Genomic Sites

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