Mutations in histone and other genes in MLL2-impaired human and mouse cells
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PROVIDER: PRJNA296116 | ENA |
REPOSITORIES: ENA
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Project description:We used human or mouse MLL2-impaired cells (including a human DSET MLL2 cell line,) as well as their parental controls, and measured mutations in histones and a few other genes that were affected in our gH2AX ChIP-Seq experiments. We found that cells lacking or having impaired MLL2 were presenting statistically signifficant, higher levels of mutations at the tested genes as compared to their parental controls. The experiments were performed using human and mouse cells. For the human cells, the parental HCT116 cells were used as control. Two different MLL2 KO clones (KO19 and KO34) and a DSET MLL2 cell line were employed. For the mouse cells, the F/F cells were used, in which both MLL2 alleles are targeted by loxp. Tamoxifen treatment for 24 hours results in the excision of both MLL2 alleles (FC/FC cells). F/F cells were treated with tamoxifen (FC/FC) or vehicle (DMSO, F/F) for 24 hours. Half of the cells were then harvested and used as controls (T0), while the other half were cultured for another 30 days (T30). Mutations after 30 days (T30) of tamoxifen/vehicle treatment were measured compared to the T0 controls. In all cases, two different pools of primers were employed. All histone genes available to target with high coverage were studied, in either human or mouse cells. For the human cells, 32 histone (HIST1H1A HIST1H1B HIST1H1C HIST1H1D HIST1H1E HIST1H1T HIST1H2AC HIST1H2AD HIST1H2AG HIST1H2AH HIST1H2AI HIST1H2AJ HIST1H2AK HIST1H2BF HIST1H2BG HIST1H2BH HIST1H2BI HIST1H2BJ HIST1H2BK HIST1H2BN HIST1H3B HIST1H3C HIST1H3D HIST1H3E HIST1H3F HIST1H3G HIST1H3H HIST1H3I HIST1H4B HIST1H4F HIST1H4J HIST2H2AC) and 6 other genes (BTG2 SGK1 MDM2 CDKN1A EGR1 RPLP0) were targeted. For the mouse cells, 21 histone (HIST1H1A HIST1H1B HIST1H1C HIST1H1D HIST1H1E HIST1H1T HIST1H2AK HIST1H2BQ HIST1H3B HIST1H3C HIST1H3F HIST1H4F HIST1H4J HIST1H4N HIST1H4N HIST2H2AA1 HIST2H2AA1 HIST2H2AA2 HIST2H2AA2 HIST2H2AC HIST2H2BB) and 6 other genes (BTG2 SGK1 MDM2 CDKN1A EGR1 RPLP0) were targeted. Processed data to be submitted to appropriate variation archive.
2016-04-13 | E-GEOD-73128 | biostudies-arrayexpress
Project description:We used human or mouse MLL2-impaired cells (including a human DSET MLL2 cell line,) as well as their parental controls, and measured mutations in histones and a few other genes that were affected in our gH2AX ChIP-Seq experiments. We found that cells lacking or having impaired MLL2 were presenting statistically signifficant, higher levels of mutations at the tested genes as compared to their parental controls.
2016-04-13 | GSE73128 | GEO
Project description:Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL), these mutations are highly recurrent and occur early during tumorigenesis, suggesting a central role in transformation. Here we show that FL/DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in germinal center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to an increase in GC B cells, whose transcriptional profile is enriched in cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage ex vivo. Loss of Mll2 combined with BCL2 deregulation, mimicking FL/DLBCL pathogenesis, leads to an increased incidence of clonal lymphoproliferations resembling the features of the human tumors. These findings suggest that early MLL2 loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events. ChIP-seq analysis of MLL2 bound regions and histone methylation (H3K4me3, H3K4me1) in normal human germinal center B cells.
2015-09-10 | E-GEOD-67494 | biostudies-arrayexpress
Project description:Epigenetic regulation by histone acetylation plays a key role in cellular homeostasis and its misregulation is associated with human disease. Histone 4 Lysine 16 acetylation (H4K16ac) serves a unique role amongst the many histone modifications as it directly affects chromatin structure1. The Male Specific Lethal (MSL) complex associated MOF/KAT8 histone acetyl transferase is responsible for bulk H4K16ac in flies and mammals. Yet, its importance during human development and a potential involvement in human pathologies remains largely unknown. Here, we uncover that pathogenic variants in MSL3, a component of the MSL complex, are causative for a new recognizable X-linked syndrome affecting Histone 4 Lysine 16 acetylation (H4K16ac) in both male and female individuals. Common clinical features of the syndrome include global developmental delay comprising profound speech delay, delayed ability to walk and craniofacial dysmorphism. Using patient-derived primary fibroblasts, we demonstrate that de novo variants or deletions of MSL3 affect the assembly and enzymatic activity of the MSL complex, hence impacting on global H4K16ac levels. Transcriptome analysis from patient cells showed misregulation of cellular pathways involved in serotonergic signaling, morphogenesis, axon guidance and cell structure. Finally, using HDAC inhibitor treatment, we can rescue expression of downregulated target genes, offering potential therapeutic avenues for MSL3-mutated patients. Taken together, we characterize a novel syndrome, named ILyADe (Impaired Lysine 16 acetylation associated disorder), which is caused by mutations of an epigenetic regulator, allowing us for the first time to unravel the crucial role of H4K16ac during human development. ILyaDe thus constitutes a new class of syndromes associated with misregulation of a single epigenetic modification caused by a genetic alteration.
2018-09-18 | PXD009317 | Pride
Project description:In this study, we constructed a tumor model of impaired inheritance of parental histones by introducing an MCM2 histone-binding domain (HBD) mutation in the breast cancer cell lines MCF-7. In this model, impaired histone inheritance resulted in dramatic epigenetic reprogramming, especially the pattern of the repressive histone mark H3K27me3, and promoted tumor growth and metastasis in vivo.
2023-05-15 | GSE201262 | GEO
Project description:Kabuki syndrome (KS) is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome described in 19811,2. In 2010, exome sequencing identified MLL2 mutations in patients with KS3. Since then, 5 studies identified a mutation in MLL2 in 56-75,6% of KS patients3-7. Here, we describe 2 KS and 1 KS-like patient with a de novo partial or complete deletion of UTX, a histone demethylase interacting with MLL2 in gene regulation. UTX locates on the X chromosome and we showed that the X chromosome with the deleted copy of UTX is preferentially inactivated despite the fact that UTX escapes X-inactivation. This study unveiled deletion of UTX as a second cause of KS and highlights the growing role of histone methylase/demethylase in MCA/MR syndrome.
2012-01-01 | GSE32567 | GEO
Project description:Kabuki syndrome (KS) is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome described in 19811,2. In 2010, exome sequencing identified MLL2 mutations in patients with KS3. Since then, 5 studies identified a mutation in MLL2 in 56-75,6% of KS patients3-7. Here, we describe 2 KS and 1 KS-like patient with a de novo partial or complete deletion of UTX, a histone demethylase interacting with MLL2 in gene regulation. UTX locates on the X chromosome and we showed that the X chromosome with the deleted copy of UTX is preferentially inactivated despite the fact that UTX escapes X-inactivation. This study unveiled deletion of UTX as a second cause of KS and highlights the growing role of histone methylase/demethylase in MCA/MR syndrome. Two patients were analysed by Agilent array CGH 244K (AMADID: 014693) Three patients DNA were analyzed by CGH on custom targeted array 44K (AMADID: 032482). Two of them were initially analyzed using 244K Whole genome Arrays (AMADID: 014693). One third patient was selected given suspicion of deletion in one of the targeted gene (KDM6A) as amplification of some exons performed in our lab to sequence this gene failed.
2012-01-01 | E-GEOD-32567 | biostudies-arrayexpress
Project description:A Phase 2, open-label, single-arm trial to evaluate the response of rucaparib in participants with various solid tumors and with deleterious mutations in Homologous Recombination Repair (HRR) genes.
| 2322588 | ecrin-mdr-crc
Project description:Histone H3.3 G34 mutations alter histone H3K36 and H3K27 methylation in cis
| PRJNA433584 | ENA
Project description:The COMPASS family catalyzes histone H3 lysine 4 (H3K4) methylation and its members are essential for regulating developmental gene expression. MLL2/COMPASS methylates H3K4 on many genes but only a subset lose expression upon MLL2 loss. To understand MLL2 -dependent transcriptional regulation, we performed a CRISPR screen in mouse embryonic stem cells (mESCs) and found that MLL2 protects developmental genes from repression by repelling PRC2 and DNA methylation machineries from these loci. Repression in the absence of MLL2 is relieved by inhibition of PRC2 and DNA methyltransferases, demonstrating that prevention of active repression and not H3K4me3 underlies their transcriptional state. DNA demethylation on such loci leads to reactivation of MLL2-dependent genes not only by removing DNA methylation but also by opening up previously CpG methylated regions for PRC2 recruitment, diluting PRC2 at Polycomb-repressed genes. These findings reveal how the context and function of these three epigenetic modifiers can orchestrate transcriptional decisions.
2020-03-17 | GSE129037 | GEO