Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques.

Abstract

Chromatin loops enable transcription-factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors such as active forms of Notch can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3D organization of cancer genomes is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B cell lymphoma, we show that beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes by instructing enhancer repositioning. Moreover, a large fraction of Notch-instructed regulatory loops form highly interacting enhancer and promoter spatial clusters termed "3D cliques." Loss- and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

• Authors: Jelena Petrovic, Yeqiao Zhou, Maria Fasolino, Naomi Goldman, Gregory W Schwartz, Maxwell R Mumbach, Son C Nguyen, Kelly S Rome, Yogev Sela, Zachary Zapataro, Stephen C Blacklow, Michael J Kruhlak, Junwei Shi, Jon C Aster, Eric F Joyce, Shawn C Little, Golnaz Vahedi, Warren S Pear, Robert B Faryabi
• Journal: Molecular cell (Mol Cell) Vol. 73 Issue 6 Pg. 1174-1190.e12 (03 21 2019) ISSN: 1097-4164 [Electronic] United States
• PMID: 30745086 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• CCND1 protein, human
• Chromatin
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• Receptors, Notch
• Cyclin D1

Topics

• Binding Sites
• Cell Lineage (genetics)
• Cell Proliferation (genetics)
• Cell Transformation, Neoplastic (genetics, metabolism, pathology)
• Chromatin (genetics, metabolism)
• Chromatin Assembly and Disassembly
• Cyclin D1 (genetics, metabolism)
• Enhancer Elements, Genetic
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• HEK293 Cells
• Humans
• Lymphoma, B-Cell (genetics, metabolism, pathology)
• Mutation
• Nucleic Acid Conformation
• Oncogenes
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Receptors, Notch (genetics, metabolism)
• Signal Transduction (genetics)
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)