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Status |
Public on Feb 19, 2024 |
Title |
Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B-cell fate decisions and accelerates development of T-cell depleted lymphomas [ATAC-seq] |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
Mutations in chromatin modifiers are a hallmark of many tumors, especially lymphomas arising from germinal center (GC) B cells. Given that these lymphoma mutations all induce aberrant gene repression, it is surprising that they often co-occur in individual patients. The most common pairing are mutations affecting CREBBP and KMT2D. Both impair enhancer activity in overlapping pathways to facilitate lymphomagenesis, hence their co-occurrence is especially puzzling. Herein, we report that combined haploinsufficiency of CREBBP and KMT2D (C+K) do indeed accelerate lymphomagenesis (vs either allele alone) and confer a more malignant phenotype. Single cell RNA-seq analysis of GC reaction showed that C+K haploinsufficiency induced aberrant GC hyperplasia by altering cell fate decisions, skewing B cells away from memory B and plasma cell differentiation and favored instead expansion of centroblasts. Integrative epigenomic studies in murine and human B cells showed that C+K deficiency particularly impairs enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for genes governing cell fate decisions induced by T cell help, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Given the impaired expression of immune synapse genes, it was notable that C+K lymphomas in mice and humans manifested significantly reduced CD8+ T cell abundance. This suggests that deficiency of the two chromatin modifiers cooperatively induced an immune evasive phenotype due to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions. These findings point to the potential need for epigenetic adjuvant therapy to augment reactivity with immunotherapy approaches in patients with C+K deficiency.
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Overall design |
ATAC-seq-based chromatin accessibility profiling for mouse GC B cells sorted from sheep red blood cell (SRBC)-immunized genetically engineered mouse models (GEMMs), which include Cg1Cre+/- (WT); Cg1Cre+/-, Crebbp fl/+ (C); Cg1Cre+/-, Kmt2d fl/+ (K); Cg1Cre+/-, Crebbp fl/+, Kmt2d fl/+ (CK); n = 4-5 mice for each genotype.
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Contributor(s) |
Chin C, Li J, Béguelin W, Melnick A |
Citation(s) |
38570506 |
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Submission date |
Feb 03, 2023 |
Last update date |
Apr 17, 2024 |
Contact name |
Christopher Russell Chin |
E-mail(s) |
chc2077@med.cornell.edu
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Phone |
3393640514
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Organization name |
Weill Cornell
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Lab |
Melnick Lab
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Street address |
413 E 69th Street, Belfer Building, BB-1462
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City |
New York City |
State/province |
NY |
ZIP/Postal code |
10021 |
Country |
USA |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (24)
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This SubSeries is part of SuperSeries: |
GSE224513 |
Cooperative super-enhancer inactivation caused by heterozygous loss of CREBBP and KMT2D skews B-cell fate decisions and accelerates development of T-cell depleted lymphomas. |
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Relations |
BioProject |
PRJNA934438 |