Decitabine treatment reveals a functional role of DNA hypomethylation in organising enhancer-promoter interactions [Promoter Capture Hi-C]

DNA methylation is one of the most important epigenetic marks and changes in DNA methylation patterns have been associated with many different types of cancer. Recently, three-dimensional (3D) genome organisation has been demonstrated to play a fundamental role in gene regulation. Determining the interplay between DNA methylation and 3D chromatin structure and function is challenging due to the extreme complexity of epigenetic regulation. To study the impact of DNA methylation on 3D genome organization, we performed a time-course of Decitabine treatment in tamoxifen-resistant MCF7 (TAMR) cells. Decitabine was applied daily for 7 days, followed by “recovery” up to 28 days and DNA methylation (EPIC), gene expression (RNA-seq) and promoter-enhancer interactions (PCHi-C) were assessed on day 7 post-Decitabine- and Vehicle-treatment and day 28 “Recovery” and Vehicle treatment in duplicate. Our data revealed a functional link between DNA hypomethylation at distal enhancer regions, enhancer-promoter interactions, and gene regulation. Overall design: To understand the role of Decitabine-induced DNA hypomethylation on 3D genome organisation, we used in situ Promoter Capture Hi-C to generate promoter-centric 3D genome maps of TAMR cells treated with Decitabine for 7 days and following 21 days of “recovery”. At the same time, we examined the genome-wide DNA methylation (EPIC Microarrays) and gene expression (RNA-seq) in the same samples.