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Series GSE224781 Query DataSets for GSE224781
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 (Cut&Run)
Organism Homo sapiens
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 Cleavage Under Targets & Release Using Nuclease (CUT&RUN) profiling of H3K4me1, H3K27ac, and H3K4me3 in isogenic human GCB-DLBCL OCI-Ly7 cell lines, which include WT, CREBBP-R1446C (C, HAT inactivating point mutation), KMT2D-KO (K), and CREBBP-R1446C + KMT2D-KO (CK); n = 2 biological replicates for each genotype.
 
Contributor(s) Chin C, Li J, Béguelin W, Melnick A
Citation(s) 38570506
Submission date Feb 07, 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)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (24)
GSM7032023 H3K4me1_WT_rep1
GSM7032024 H3K4me1_WT_rep2
GSM7032025 H3K4me1_C_rep1
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 PRJNA934525

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SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE224781_ly7.deseq.promoter.dds.Rdata.gz 6.5 Mb (ftp)(http) RDATA
GSE224781_ly7.h3k27ac.dba.Rdata.gz 111.9 Mb (ftp)(http) RDATA
GSE224781_ly7.h3k4me1.dba.Rdata.gz 48.0 Mb (ftp)(http) RDATA
GSE224781_ly7.h3k4me3.dba.Rdata.gz 106.7 Mb (ftp)(http) RDATA
GSE224781_ly7_SuperStitched.table.txt.gz 68.3 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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