Cohesin mediated 3D genome structure defines Neuroblastoma cell subtypes and their plasticity

Authors

• JY Kang
• Z Liu
• M Sun
• CJ Thiele

Abstract

Neuroblastoma is highly heterogenous marked by distinct epigenetic profiles with distinct 3D genome organization. In addition to its role in DNA replication/damage, Cohesin mediates the looping structure between promoters and enhancers to regulate gene expression. Our study aims to evaluate the role of cohesin in control of cell-type specific super-enhancer networks in neuroblastoma.
Data mining using R2 database, Cohesin was significantly over-expressed in NB tumors compared to neural crest cells or adrenal gland and were significantly associated with poor event-free/overall survival. Studies evaluating H3K27Ac have shown distinct super-enhancer landscapes between MES/ADRN cell types. Our Cohesin ChIP-seq data show cohesin binding pattern between these two cell subtypes is very distinct, with cell type specific enhancers and promoters bound by cohesin subunits. Homer de novo motif scan of cohesin binding site in MES cell line identified well known MES specific CRC TF as highest ranked motif, whereas Homer de novo motif scan of cohesin binding site in ADRN cell line identified well known ADRN specific CRC TF as highest ranked motif. We identified that MES specific genes were differentially expressed after RAD21 knockdown in MES cells. These results indicate the possibility of cohesin bound at cell type specific enhancer-promoter regions regulating its target genes through enhancer/promoter looping.
In this study we are defining the molecular mechanisms underlying regulation of 3D genome structure neuroblastoma, which is crucial for understanding how neuroblastoma cell types acquire and stabilize their cellular identity and the basic mechanisms involved in cell state changes during therapeutic interventions and differentiation.

Scientific Focus Area: Chromosome Biology

This page was last updated on Monday, September 25, 2023