NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers
Open accessAbstract
The main oncogenic driver in T-lymphoblastic leukemia is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase-inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1-binding sites are insensitive to gamma-secretase inhibitors. Here, we demonstrate that fewer than 10% of NOTCH1-binding sites show dynamic changes in NOTCH1 occupancy when T-lymphoblastic leukemia cells are toggled between the Notch-on and -off states with gamma-secretase inhibiters. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T-cell development and in T-lymphoblastic leukemia, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1-binding sites cooccupy chromatin domains defined by constitutive binding of CCCTC binding factor, which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in superenhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of superenhancers and in the promoters of Notch target genes. These findings link regulation of superenhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes.
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Gene activation by NOTCH signaling in T-cells is restricted to genes that occur within the same CTCF-CTCF loops as NOTCH-dependent enhancers.
“The effect of insulated neighborhoods on signal-responsive gene expression also supports the concept of insulation; gene activation by NOTCH signaling in T-cells was found to be restricted to genes that occur within the same CTCF-CTCF loops as NOTCH-dependent enhancers (Wang et al., 2014).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Wang et al., 2014
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- Authors
- Wang, H., Zang, C., Taing, L., Arnett, K. L., Wong, Y. J., Pear, W. S., Blacklow, S. C., Liu, X. S., & Aster, J. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-12-27
- Volume
- 111
- Issue
- 2
- Pages
- 705-710
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3896193
- OpenAlex
- W1996258482
- Cited by
- 252
- References
- 37
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 21 · 2023: 29 · 2022: 23 · 2021: 19 · 2020: 23 · 2019: 27 · 2018: 22 · 2017: 18 · 2016: 25 · 2015: 21 · 2014: 8 · 2013: 1
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007627)
- National Cancer Institute (P01CA119070)
- National Institute of General Medical Sciences (R01GM099409)
- National Institute of Allergy and Infectious Diseases (R01AI047833)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- Notch1, RBPJ, super-enhancers, T-cell acute lymphoblastic leukemia, gamma-secretase inhibitors, distal enhancers, RUNX1, CD127, CTCF, H3K27ac, chromatin accessibility, transcriptional regulation, Notch target genes, transcription factor binding sites
- MeSH terms
- Binding Sites, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Luciferases, Plasmids, Promoter Regions, Genetic, Signal Transduction, DNA Primers, Receptors, Interleukin-7, Cell Line, Tumor, Multiprotein Complexes, Chromatin Immunoprecipitation, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Receptor, Notch1, Real-Time Polymerase Chain Reaction
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