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DOT1L shapes ncPRC1-target gene repression to maintain cell identity of DLBCL [CUT&Tag]

ABSTRACT: DOT1L inhibition leads to a loss of H2AK119ub1 in different GC B-DLBCL cell lines. To determine whether this loss is global or gene specific, performed H2AK119ub1 and H3K27me3 CUT&Tag in the Oci-Ly7 cell line following six days of treatment with DMSO or DOT1Li. As reference, we used a doxycycline-inducible knockdown of USP7 due to its role in ncPRC1-mediated deposition of H2AK119ub1 in Oci-Ly7 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327306 | GEO | 2026/06/19

REPOSITORIES: GEO

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DOT1L shapes ncPRC1-target gene repression to maintain cell identity of DLBCL [RNA-Seq]

Project description:Germinal center (GC) B cell-like diffuse large B cell lymphoma (GCB-DLBCL) depends on the cooperative activity of the histone methyltransferases DOT1L and EZH2 to maintain its pro-proliferative GCB cell identity while repressing plasma cell (PC) differentiation. To explore the mechanisms underlying the co-dependency between DOT1L and EZH2 in GCB-DLBCL, we performed an EZH2 inhibition (EZH2i)-anchored genome-wide CRISPR interference screen and identified multiple candidate genes encoding components of non-canonical (nc) PRC1 complexes, including USP7, KDM2B, RING1, and PCGF1. We identified USP7 as potential direct target of DOT1L, whose downregulation was associated with increased EZH2i sensitivity in multiple GCB-DLBCL cell lines. Furthermore, we observed that DOT1L influences the composition of chromatin-bound ncPRC1 complexes and regulates, in part, the deposition of H2AK119 monoubiquitination (H2AK119ub1) at gene promoters co-occupied by H3K27me3, here defined as PRC1/2 target genes. These PRC1/2 targets were specifically enriched in PC signature genes, whose derepression was associated with DOT1L inhibition (DOT1Li)-mediated loss of H2AK119ub1. This study reveals novel insights into the role of DOT1L and its functional co-dependence with EZH2 in maintaining GCB identity in DLBCL, supporting a model in which concurrent reduction of H2AK119ub1 and H3K27me3 promotes differentiation toward an anti-proliferative, plasma cell–like state.

2026-06-19 | GSE327307 | GEO

DOT1L and EZH2 cooperatively repress PRC2 targets to maintain the GC B cell identity in DLBCL [RNA-seq]

Project description:Previous published data suggested that DOT1L indirectly represses PRC2 target genes in murine B cell model. To address whether this relationship persists in human GCB-DLBCL, by integration of transcriptomic and epigenetic analysis, we defined the candidate direct targets of PRC2. GSEA of this genes list showed that DOT1L inhibition was able to significantly derepress candidate PRC2-target genes in Oci-Ly7 and Oci-Ly8. This effect was also observed upon combination treatment of DOT1Li and EZH2i, suggesting that DOT1L indirectly regulates the repression of PRC2 target genes. Moreover, it has been established that in the absence of Dot1l or Ezh2, GC B cells cannot maintain their identity and instead differentiate into a dysfunctional plasma cell-like state. We therefore, investigated whether the combined inhibition of DOT1L and EZH2 enhances plasma cell differentiation. We first established differentiation-state specific signatures unique for NBC, CB, MBC, PB, and BMPC using the GenomicScape database. Unsupervised clustering of the GSVA scores revealed that all the cell lines treated with the combination treatment were clustered together and gained a BMPC signature at the expense of a CB-signature. This crosstalk between DOT1L and EZH2 appeared to be conserved among different GCB-DLBCL cell lines and was independent of their responsiveness to the treatments.

2025-01-22 | GSE277665 | GEO

(ChIP-seq) USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

Project description:Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.

2022-11-08 | GSE193014 | GEO

(ChIP-seq) USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

2022-11-08 | GSE193013 | GEO

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3 [ChIP-seq]

2022-11-12 | GSE217658 | GEO

(RNA-seq) USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

2022-11-08 | GSE193019 | GEO

DOT1L and EZH2 cooperatively repress PRC2 targets to maintain the GC B cell identity in DLBCL [ChIP-seq]

Project description:To determine whether DOT1L promotes repression of PRC2 target genes independently of EZH2, we performed H3K27me3 ChIP-seq on untreated responder Oci-Ly7 and non-responder Oci-Ly8 cell lines, and selected the top 10% of protein-coding genes with the highest H3K27me3 read counts from transcription start site +3 kilobases for subsequent analysis.

2025-01-22 | GSE277666 | GEO

Transcriptional profiling of chemical Dot1L inhibition during reprogramming to induced pluripotent stem cells

Project description:Three independent transcriptional profiling experiments were performed to ascertain how Dot1L affects cell fate change. 1) In a timecoure ("Tc"), reprogramming mouse embryonic fibroblasts were treated with DMSO control or Dot1L inhibitor (Dot1Li -SGC0946) for 2 or 4 days. Surprisingly, despite the enrichment of H3K79me2 on thousands of actively transcribed genes, Dot1L inhibition (Dot1Li) results in few changes in steady state mRNA levels during reprogramming, the majority of which are spuriously upregulated. 2) To determine if Dot1Li increased reprogramming beyond the mesenchymal to epithelial transition (MET) that occurs early in reprogramming when starting from MEFs, reprogramming cells were sorted ("Sort") for surface CDH1 expression, and then treated with Dot1Li or control. Dot1Li increased reprogramming efficiency of both CDH1- and CDH1+ populations to a similar extent and few genes were DE. 3) To assess if Dot1Li increased pluripotency acquisition beyond CDH1 upregulation, CDH1 or empty vector was expressed ("Exp") in reprogramming cells. CDH1 expression did not initiate MET, or enhance reprogramming.

2021-04-30 | GSE160580 | GEO

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

Project description:USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3

| PRJNA794139 | ENA

Retroviral overexpression or siRNA mediated knockdown of FOXP1 in DLBCL cell lines and primary human B cells

Project description:To provide insight into the role of and target genes of the transcription factor FOXP1 in mature human B cells and in B cell non-Hodkgin lymhomas, we performed gene expression microarray studies, upon ectopic overexpression or silencing of FOXP1 in these cells. human memory B cells from 2 separate donors were transduced with LZRS-FOXP1-IRES-YFP or LZRS-IRES-YFP (negative control); DLBCL cell lines OCI-Ly1, OCI-Ly7, and OCI-Ly10 were transduced with LZRS-FOXP1-IRES-YFP or LZRS-IRES-YFP (negative control); DLBCL cell lines OCI-Ly1, OCI-Ly7, and OCI-Ly10 were transiently transfected with siRNA targeting FOXP1 or sigenome non-targeting siRNA (negative control), using the Lonza nucleofection system.

2014-10-24 | E-GEOD-51382 | biostudies-arrayexpress

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