Deciphering the Genomic Targets of Alkylating Polyamide Conjugates Using High-Throughput Sequencing

Chandran, Anandhakumar

doi:10.1007/978-981-10-6547-7_4

Cited by 2 publications

(2 citation statements)

References 47 publications

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“…Extensive analysis of the cognate binding sites clearly showed that SAHA–PIP G binds to the WSWSW motif as expected based on the structure and the predicted binding rule of PIP. So far, PIP binding specificity has been demonstrated using cell extracts (Chandran et al, 2016). Therefore, this is the first confirmation that SAHA–PIP could specifically recognize its binding sequence not only in vitro but also at the genome‐wide level in cells, thereby implying the potential use of PIP for site‐specific regulation of genes in vivo.…”

Section: Discussionmentioning

confidence: 99%

Targeted epigenetic modulation using a DNA‐based histone deacetylase inhibitor enhances cardiomyogenesis in mouse embryonic stem cells

Lee

Taniguchi

et al. 2020

Journal Cellular Physiology

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The epigenome has an essential role in orchestrating transcriptional activation and modulating key developmental processes. Previously, we developed a library of pyrrole‐imidazole polyamides (PIPs) conjugated with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, for the purpose of sequence‐specific modification of epigenetics. Based on the gene expression profile of SAHA‐PIPs and screening studies using the α‐myosin heavy chain promoter‐driven reporter and SAHA–PIP library, we identified that SAHA–PIP G activates cardiac‐related genes. Studies in mouse ES cells showed that SAHA–PIP G could enhance the generation of spontaneous beating cells, which is consistent with upregulation of several cardiac‐related genes. Moreover, ChIP‐seq results confirmed that the upregulation of cardiac‐related genes is highly correlated with epigenetic activation, relevant to the sequence‐specific binding of SAHA–PIP G. This proof‐of‐concept study demonstrating the applicability of SAHA–PIP not only improves our understanding of epigenetic alterations involved in cardiomyogenesis but also provides a novel chemical‐based strategy for stem cell differentiation.

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Section: Discussionmentioning

confidence: 99%

Targeted epigenetic modulation using a DNA‐based histone deacetylase inhibitor enhances cardiomyogenesis in mouse embryonic stem cells

Lee

Taniguchi

et al. 2020

Journal Cellular Physiology

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“…Genome-wide binding of these tripartite molecules is captured by photo-induced crosslinking followed by biotin-enabled enrichment and unbiased NGS sequencing of the conjugated genomic loci [23,24]. The ability to induce rapid crosslinking at the desired time point distinguishes COSMIC-seq from continuous and uncontrolled alkylation-dependent DNA conjugations that have been used to query genome-wide binding of polyamides [25].…”

Section: An Im/py Pair Binds G•c; Py/im Binds C•g and Py/py Pairs Bomentioning

confidence: 99%

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

Finn¹,

Bhimsaria²,

Ali³

et al. 2020

Preprint

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Regulating desired loci in the genome with sequence specific DNA binding molecules is a major goal for the development of precision medicine. Pyrrole imidazole (Py Im) polyamides are synthetic molecules that can be rationally designed to target specific DNA sequences to both disrupt and recruit transcriptional machinery. While in vitro binding has been extensively studied, in vivo effects are often difficult to predict using current models of DNA binding. Determining the impact of genomic architecture and the local chromatin landscape on polyamide DNA sequence specificity remains an unresolved question that impedes their effective deployment in vivo. In this report we identified polyamide DNA interaction sites across the entire genome, by covalently crosslinking and capturing these events in the nuclei of human LNCaP cells. This method, termed COSMIC seq, confirms the ability of hairpin polyamides, with similar architectures but differing at a single ring position, to retain in vitro specificities and display distinct genome-wide binding profiles. These results underpin the development of Py Im polyamides as DNA targeting molecules that mediate their regulatory or remedial functions at desired genomic loci.

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Deciphering the Genomic Targets of Alkylating Polyamide Conjugates Using High-Throughput Sequencing

Cited by 2 publications

References 47 publications

Targeted epigenetic modulation using a DNA‐based histone deacetylase inhibitor enhances cardiomyogenesis in mouse embryonic stem cells

Targeted epigenetic modulation using a DNA‐based histone deacetylase inhibitor enhances cardiomyogenesis in mouse embryonic stem cells

Single position substitution of hairpin pyrrole-imidazole polyamides imparts distinct DNA-binding profiles across the human genome

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