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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target [Seq]

ABSTRACT: Multiple myeloma (MM) is a hematopoietic malignancy characterised by the accumulation of neoplastic post-germinal centre, isotype-switched, long-lived plasma cell within the bone marrow. In genetic and clinical terms MM is highly heterogeneous and remains fatal. Here we present the first epigenomic map of MM derived from freshly isolated bone marrow plasma cells from four patients. Using ChIP- and RNA-sequencing we define a set of silent H3K27me3 targets, active genes bearing H3K4me3, and bivalent genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE53215 | GEO | 2015/12/31

SECONDARY ACCESSION(S): PRJNA231147

REPOSITORIES: GEO

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Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target [Seq]

Project description:Multiple myeloma (MM) is a hematopoietic malignancy characterised by the accumulation of neoplastic post-germinal centre, isotype-switched, long-lived plasma cell within the bone marrow. In genetic and clinical terms MM is highly heterogeneous and remains fatal. Here we present the first epigenomic map of MM derived from freshly isolated bone marrow plasma cells from four patients. Using ChIP- and RNA-sequencing we define a set of silent H3K27me3 targets, active genes bearing H3K4me3, and bivalent genes. Examination of 2 different histone modifications in four Multiple myeloma patients and two normal plasma cells samples. A single patient RNA-seq sample was also examined.

2015-12-31 | E-GEOD-53215 | biostudies-arrayexpress

2015-12-31 | GSE69251 | GEO

Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.

Project description:Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

| S-EPMC4872750 | biostudies-literature

Project description:in this study we define an epigenomic profile of PRC2 (H3K27me3 and bivalent) tragets in four newly diagnosed MM patients. Using Oncomine database we demonstarte that PRC2 targets are underexpressed with advanced ISS stages and correlated to poor outcome. Pharmacological inhibition of UNC1999 showed anti-myeloma potential in vitro by activating the expression genes related to apoptosis and cell differenatiation. In this array the differences between the gene expression profiles of samll molecule inhibitor (UNC1999) of EZH2 and the control (UNC2400) have been tested. So multiple myeloma cell line INA-6 was treated with 2Î¼M of UNC1999 and UNC2400. This design contains three biological replicates.

2015-12-31 | E-GEOD-69251 | biostudies-arrayexpress

Isotype-based plasma cell subsets display differential niches requirements in the bone marrow

Project description:Bone marrow long-lived plasma cells are essential for long-term protection against infection and their persistence within this organ relies on interactions with Cxcl12-expressing stromal cells that are still not clearly identified. Here, using single cell RNAseq and in silico transinteractome analyses we identified LepR+ mesenchymal cells as the stromal cell subset most likely to interact with plasma cells within the bone marrow. Moreover, we demonstrated that depending on the isotype they express, plasma cells may use different set of integrins and adhesion molecules to interact with these stromal cells. Altogether, our results constitute an unprecedented characterization of plasma cell subset stromal niches and open new avenues for the specific targeting of bone marrow plasma cells based on their isotype.

2023-06-30 | GSE228543 | GEO

Histone 3 Lysine 27 Trimethylation Signature in Breast Cancer.

Project description:Cancer development and progression rely on complicated genetic and also epigenetic changes which regulate gene expression without altering the DNA sequence. Epigenetic mechanisms such as DNA methylation, histone modifications, and regulation by lncRNAs alter protein expression by either promoting gene transcription or repressing it. The presence of so-called chromatin modification marks at various gene promoters and gene bodies is associated with normal cell development but also with tumorigenesis and progression of different types of cancer, including the most frequently diagnosed breast cancer. This review is focused on the significance of one of the abundant post-translational modifications of histone 3- trimethylation of lysine 27 (H3K27me3), which was shown to participate in tumour suppressor genes' silencing. Unlike other reviews in the field, here the overview of existing evidence linking H3K27me3 status with breast cancer biology and the tumour outcome is presented especially in the context of diverse breast cancer subtypes. Moreover, the potential of agents that target H3K27me3 for the treatment of this complex disease as well as H3K27 methylation in cross-talk with other chromatin modifications and lncRNAs are discussed.

| S-EPMC8657745 | biostudies-literature

Whole-genome analysis of histone H3 lysine 27 trimethylation in Arabidopsis.

Project description:Trimethylation of histone H3 lysine 27 (H3K27me3) plays critical roles in regulating animal development, and in several cases, H3K27me3 is also required for the proper expression of developmentally important genes in plants. However, the extent to which H3K27me3 regulates plant genes on a genome-wide scale remains unknown. In addition, it is not clear whether the establishment and spreading of H3K27me3 occur through the same mechanisms in plants and animals. We identified regions containing H3K27me3 in the genome of the flowering plant Arabidopsis thaliana using a high-density whole-genome tiling microarray. The results suggest that H3K27me3 is a major silencing mechanism in plants that regulates an unexpectedly large number of genes in Arabidopsis (~4,400), and that the maintenance of H3K27me3 is largely independent of other epigenetic pathways, such as DNA methylation or RNA interference. Unlike in animals, where H3K27m3 occupies large genomic regions, in Arabidopsis, we found that H3K27m3 domains were largely restricted to the transcribed regions of single genes. Furthermore, unlike in animals systems, H3K27m3 domains were not preferentially associated with low-nucleosome density regions. The results suggest that different mechanisms may underlie the establishment and spreading of H3K27me3 in plants and animals.

| S-EPMC1852588 | biostudies-literature

The CHD3 remodeler PICKLE promotes trimethylation of histone H3 lysine 27.

Project description:CHD3 proteins are ATP-dependent chromatin remodelers that contribute to repression of developmentally regulated genes in both animal and plant systems. In animals, this repression has been linked to a multiple subunit complex, Mi-2/NuRD, whose constituents include a CHD3 protein, a histone deacetylase, and a methyl-CpG-binding domain protein. In Arabidopsis, PICKLE (PKL) codes for a CHD3 protein that acts during germination to repress expression of seed-associated genes. Repression of seed-associated traits is promoted in pkl seedlings by the plant growth regulator gibberellin (GA). We undertook a microarray analysis to determine how PKL and GA act to promote the transition from seed to seedling. We found that PKL and GA act in separate pathways to repress expression of seed-specific genes. Comparison of genomic datasets revealed that PKL-dependent genes are enriched for trimethylation of histone H3 lysine 27 (H3K27me3), a repressive epigenetic mark. Chromatin immunoprecipitation studies demonstrate that PKL promotes H3K27me3 in both germinating seedlings and in adult plants but do not identify a connection between PKL-dependent expression and acetylation levels. Taken together, our analyses illuminate a new pathway by which CHD3 remodelers contribute to repression in eukaryotes.

| S-EPMC2504882 | biostudies-literature

Origins and diversity of pan-isotype human bone marrow plasma cells

Project description:Origins and diversity of pan-isotype human bone marrow plasma cells

| PRJNA1094593 | ENA

Histone H3 Lysine 4 and 27 Trimethylation Landscape of Human Alzheimer's Disease.

Project description:Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer's disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD. To investigate histone H3 modifications in AD, we compared the genome-wide distributions of H3K4me3 and H3K27me3 in entorhinal cortices from severe sporadic AD patients and from age-matched healthy individuals of both sexes. AD samples were characterized by typical average levels and distributions of the H3K4me3 and H3K27me3 signals. However, AD patients showed a lower H3K4me3 and higher H3K27me3 signal, particularly in males. Interestingly, the genomic sites found differentially trimethylated at the H3K4 between healthy and AD samples involve promoter regions of genes belonging to AD-related pathways such as glutamate receptor signaling. The signatures of H3K4me3 and H3K27me3 identified in AD patients validate the role of epigenetic chromatin remodeling in neurodegenerative disease and shed light on the genomic adaptive mechanisms involved in AD.

| S-EPMC8870338 | biostudies-literature

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