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Series GSE224512 Query DataSets for GSE224512
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
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.
 
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.
 
Contributor(s) Chin C, Li J, Béguelin W, Melnick A
Citation(s) 38570506
Submission date Feb 03, 2023
Last update date Apr 17, 2024
Contact name Christopher Russell Chin
E-mail(s) chc2077@med.cornell.edu
Phone 3393640514
Organization name Weill Cornell
Lab Melnick Lab
Street address 413 E 69th Street, Belfer Building, BB-1462
City New York City
State/province NY
ZIP/Postal code 10021
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (24)
GSM7025393 GCB_WT_rep1 [WT_R1]
GSM7025394 GCB_WT_rep2 [WT_R2]
GSM7025395 GCB_WT_rep3 [WT_R3]
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.
Relations
BioProject PRJNA934438

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Supplementary file Size Download File type/resource
GSE224512_RAW.tar 788.5 Mb (http)(custom) TAR (of BIGWIG)
GSE224512_consensus_peaks.mLb.clN.featureCounts.txt.gz 2.5 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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