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

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.

• Authors: Mariateresa Fulciniti, Charles Y Lin, Mehmet K Samur, Michael A Lopez, Irtisha Singh, Matthew A Lawlor, Raphael E Szalat, Christopher J Ott, Herve' Avet-Loiseau, Kenneth C Anderson, Richard A Young, James E Bradner, Nikhil C Munshi
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 13 Pg. 3693-3705.e6 (12 26 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30590042 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

• (+)-JQ1 compound
• Azepines
• E2F1 Transcription Factor
• Transcription Factor DP1
• Triazoles

Topics

• Animals
• Azepines (pharmacology)
• Carcinogenesis (genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• E2F1 Transcription Factor (metabolism)
• Enhancer Elements, Genetic
• Gene Expression Regulation, Neoplastic
• Humans
• Mice, SCID
• Multiple Myeloma (genetics, pathology)
• Promoter Regions, Genetic
• Protein Binding
• Protein Domains
• Protein Multimerization
• Transcription Factor DP1 (metabolism)
• Transcriptome (genetics)
• Triazoles (pharmacology)