Department of Chemistry, Institute for Structural and Molecular Biology, University College London, 20 Gordon Street, London, WC1H 0AJ, UK.
UCL Cancer Institute, London, UK.
Angew Chem Int Ed Engl. 2019 May 13;58(20):6620-6624. doi: 10.1002/anie.201901139. Epub 2019 Apr 12.
Controlling the functional dynamics of DNA within living cells is essential in biomedical research. Epigenetic modifications such as DNA methylation play a key role in this endeavour. DNA methylation can be controlled by genetic means. Yet there are few chemical tools available for the spatial and temporal modulation of this modification. Herein, we present a small-molecule approach to modulate DNA methylation with light. The strategy uses a photo-tuneable version of a clinically used drug (5-aza-2'-deoxycytidine) to alter the catalytic activity of DNA methyltransferases, the enzymes that methylate DNA. After uptake by cells, the photo-regulated molecule can be light-controlled to reduce genome-wide DNA methylation levels in proliferating cells. The chemical tool complements genetic, biochemical, and pharmacological approaches to study the role of DNA methylation in biology and medicine.
在生物医学研究中，控制活细胞内 DNA 的功能动态至关重要。表观遗传修饰，如 DNA 甲基化，在这方面起着关键作用。DNA 甲基化可以通过遗传手段来控制。然而，用于这种修饰的时空调节的化学工具却很少。本文中，我们提出了一种用光来调节 DNA 甲基化的小分子方法。该策略使用一种临床使用的药物（5-氮杂-2'-脱氧胞苷）的光可调版本来改变甲基转移酶（将 DNA 甲基化的酶）的催化活性。细胞摄取后，光调控分子可以用光控制来降低增殖细胞中的全基因组 DNA 甲基化水平。这种化学工具补充了遗传、生化和药理学方法，用于研究 DNA 甲基化在生物学和医学中的作用。
