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Advancing Development of Synthetic Gene Regulators

With the Power of High-Throughput Sequencing in Chemical Biology

  • Anandhakumar Chandran

Part of the Springer Theses book series (Springer Theses)

About this book

Introduction

This book focuses on an “outside the box” notion by utilizing the powerful applications of next-generation sequencing (NGS) technologies in the interface of chemistry and biology. In personalized medicine, developing small molecules targeting a specific genomic sequence is an attractive goal. N-methylpyrrole (P)–N-methylimidazole (I) polyamides (PIPs) are a class of small molecule that can bind to the DNA minor groove. First, a cost-effective NGS (ion torrent platform)-based Bind-n-Seq was developed to identify the binding specificity of PIP conjugates in a randomized DNA library. Their biological influences rely primarily on selective DNA binding affinity, so it is important to analyze their genome-wide binding preferences. However, it is demanding to enrich specifically the small-molecule-bound DNA without chemical cross-linking or covalent binding in chromatinized genomes. Herein is described a method that was developed using high-throughput sequencing to map the differential binding sites and relative enriched regions of non-cross-linked SAHA-PIPs throughout the complex human genome. SAHA-PIPs binding motifs were identified and the genome-level mapping of SAHA-PIPs-enriched regions provided evidence for the differential activation of the gene network. A method using high-throughput sequencing to map the binding sites and relative enriched regions of alkylating PIP throughout the human genome was also developed. The genome-level mapping of alkylating the PIP-enriched region and the binding sites on the human genome identifies significant genomic targets of breast cancer. It is anticipated that this pioneering low-cost, high through-put investigation at the sequence-specific level will be helpful in understanding the binding specificity of various DNA-binding small molecules, which in turn will be beneficial for the development of small-molecule-based drugs targeting a genome-level sequence. 

Keywords

Next Generation Sequencing small molecules targeting specific genomic sequence Bind-n-Seq high-throughput sequencing PIP

Authors and affiliations

  • Anandhakumar Chandran
    • 1
  1. 1.Department of Chemistry, Graduate School of ScienceKyoto UniversityKyotoJapan

Bibliographic information

  • DOI https://doi.org/10.1007/978-981-10-6547-7
  • Copyright Information Springer Nature Singapore Pte Ltd. 2018
  • Publisher Name Springer, Singapore
  • eBook Packages Chemistry and Materials Science
  • Print ISBN 978-981-10-6546-0
  • Online ISBN 978-981-10-6547-7
  • Series Print ISSN 2190-5053
  • Series Online ISSN 2190-5061
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