Non-overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma
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Author(s)
Fulciniti, Mariateresa
Lin, Charles Y.
Samur, Mehmet K.
Lopez, Michael A.
Singh, Irtisha
Lawlor, Matthew A.
Szalat, Raphael E.
Ott, Christopher J.
Avet-Loiseau, Herve’
Anderson, Kenneth C.
Date Issued
December 2018
Journal
Cell Reports
Publisher
Elsevier BV
Citation
Fulciniti, Mariateresa et al. “Non-Overlapping Control of Transcriptome by Promoter- and Super-Enhancer-Associated Dependencies in Multiple Myeloma.” Cell Reports 25, 13 (December 2018): 3693–3705.e6 © 2018 Elsevier
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2018.12.016
