Characterizing the interplay between super enhancers and chromatin interactions in cancer

• Main Author: Choudhary, Ruchi
• Other Authors: Melissa Jane Fullwood
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences; Cancer; Super enhancers; Chromatin interactions; 3D genome organization
• Online Access: https://hdl.handle.net/10356/173896
• Institution: Nanyang Technological University

Chromatin interactions are vital for regulating gene expression by connecting distal regulatory elements like enhancers and super enhancers (SEs) with target genes. Our study aims to uncover vulnerabilities in these complex networks and identify potential cancer treatment targets. We propose that SEs use chromatin loops to drive gene transcription, and altering chromatin interactions can downregulate SEs and disrupt enhancer-promoter interactions controlling oncogenes and tumor progression. We associated SEs with chromatin interactions in acute myeloid leukemia (AML) and nasopharyngeal cancer (NPC) samples. Our previous research showed that increased c-MYC expression heightens chromatin interactions. Elevated c-MYC levels in cancer may enhance chromatin interactions between SEs and promoters, driving oncogenic pathways. Using HiChIP experiments in five human cell lines, we discovered multiple transcription factor (TF) clusters regulating chromatin interactions between SEs/enhancers and promoters, with one hub enriched in c-MYC and YY1. Targeting a single TF cluster may be insufficient to disrupt these SE/enhancer-promoter loops. Simultaneously targeting multiple TF clusters could be necessary to perturb these dysregulated networks in diseases like cancer. This suggests a novel therapeutic strategy using epigenetic drugs to inhibit multiple TFs from different clusters, exploiting the vulnerability created by disrupting SE/enhancer-promoter interactions.