Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma

• Main Authors: Fulciniti, Mariateresa (Author), Lin, Charles Y. (Author), Samur, Mehmet K. (Author), Lopez, Michael A. (Author), Singh, Irtisha (Author), Lawlor, Matthew A. (Author), Szalat, Raphael E. (Author), Ott, Christopher J. (Author), Avet-Loiseau, Herve' (Author), Anderson, Kenneth C. (Author), Young, Richard A. (Author), Bradner, James E. (Author), Munshi, Nikhil C. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: Elsevier BV, 2020-11-02T23:31:10Z.
• Subjects: Article
• Online Access: Get fulltext

The relationship between promoter proximal transcription factor-associated gene expression and super-enhancer-driven transcriptional programs are not well defined. However, their distinct genomic occupancy suggests a mechanism for specific and separable gene control. We explored the transcriptional and functional interrelationship between E2F transcription factors and BET transcriptional co-activators in multiple myeloma. We found that the transcription factor E2F1 and its heterodimerization partner DP1 represent a dependency in multiple myeloma cells. Global chromatin analysis reveals distinct regulatory axes for E2F and BETs, with E2F predominantly localized to active gene promoters of growth and/or proliferation genes and BETs disproportionately at enhancer-regulated tissue-specific genes. These two separate gene regulatory axes can be simultaneously targeted to impair the myeloma proliferative program, providing an important molecular mechanism for combination therapy. This study therefore suggests a sequestered cellular functional control that may be perturbed in cancer with potential for development of a promising therapeutic strategy.