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Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254366 | GEO | 2024/09/01

REPOSITORIES: GEO

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Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [ChIP-Seq]

Project description:BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors is uniquely presenting epigenomic phenotypes. Nonetheless, the traditional epigenomic therapeutic agent, 5-azacitidine, which inhibits DNA methyltransferase activity, did not yield sufficient improvements in the efficacies of BRAFV600E CRC in vivo. We utilized a patient-derived xenograft model and confirmed an effective reduction of DNA methylation levels upon 5-azacitidine treatment yet failed to restore gene expression patterns. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon the profound decrease in DNA methylation by azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around hypomethylated regions. Our findings suggested a compensatory increase in repressive histone mark, H3K27 trimethylation, around treatment-induced hypomethylated regions, which suggests the involvement of polycomb repressive complex (PRC) activity around the genome with lost DNA methylation, therefore maintaining the suppression of key genes. Combined inhibition of PRC activity through EZH2 inhibitor with azacitidine treatment additively improved efficacies in BRAFV600E CRC cells. In conclusion, DNA hypermethylation exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.

2024-09-03 | GSE254365 | GEO

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC [ATAC-seq]

2024-09-01 | GSE254604 | GEO

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [RNA-Seq]

2024-09-01 | GSE254279 | GEO

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC.

Project description:Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC.

| PRJNA1070254 | ENA

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [ChIP-Seq]

Project description:Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [ChIP-Seq]

| PRJNA1070257 | ENA

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [RNA-Seq]

Project description:Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC. [RNA-Seq]

| PRJNA1069614 | ENA

Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC [ATAC-seq]

Project description:Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated CRC [ATAC-seq]

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Investigating crosstalk between H3K27 acetylation and H3K4 trimethylation in CRISPR/dCas-based epigenome editing and gene activation.

Project description:Epigenome editing methods enable the precise manipulation of epigenetic modifications, such as histone posttranscriptional modifications (PTMs), for uncovering their biological functions. While histone PTMs have been correlated with certain gene expression status, the causalities remain elusive. Histone H3 Lysine 27 acetylation (H3K27ac) and histone H3 Lysine 4 trimethylation (H3K4me3) are both associated with active genes, and located at active promoters and enhancers or around transcriptional start sites (TSSs). Although crosstalk between histone lysine acetylation and H3K4me3 has been reported, relationships between specific epigenetic marks during transcriptional activation remain largely unclear. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/dCas-based epigenome editing methods, we discovered that the ectopic introduction of H3K27ac in the promoter region lead to H3K4me3 enrichment around TSS and transcriptional activation, while H3K4me3 installation at the promoter cannot induce H3K27ac increase and failed to activate gene expression. Blocking the reading of H3K27ac by BRD proteins using inhibitor JQ1 abolished H3K27ac-induced H3K4me3 installation and downstream gene activation. Furthermore, we uncovered that BRD2, not BRD4, mediated H3K4me3 installation and gene activation upon H3K27ac writing. Our studies revealed the relationships between H3K27ac and H3K4me3 in gene activation process and demonstrated the application of CRISPR/dCas-based epigenome editing methods in elucidating the crosstalk between epigenetic mechanisms.

| S-EPMC8342468 | biostudies-literature

Decreased H3K27 and H3K4 trimethylation on mortal chromosomes in distributed stem cells.

Project description:The role of immortal DNA strands that co-segregate during mitosis of asymmetrically self-renewing distributed stem cells (DSCs) is unknown. Previously, investigation of immortal DNA strand function and molecular mechanisms responsible for their nonrandom co-segregation was precluded by difficulty in identifying DSCs and immortal DNA strands. Here, we report the use of two technological innovations, selective DSC expansion and establishment of H2A.Z chromosomal asymmetry as a specific marker of 'immortal chromosomes,' to investigate molecular properties of immortal chromosomes and opposing 'mortal chromosomes' in cultured mouse hair follicle DSCs. Although detection of the respective suppressive and activating H3K27me3 and H3K4me3 epigenetic marks on immortal chromosomes was similar to randomly segregated chromosomes, detection of both was lower on mortal chromosomes destined for lineage-committed sister cells. This global epigenomic feature of nonrandom co-segregation may reveal a mechanism that maintains an epigenome-wide 'poised' transcription state, which preserves DSC identity, while simultaneously activating sister chromosomes for differentiation.

| S-EPMC4649838 | biostudies-literature

Mapping of H3K4 and H3K27 trimethylation in zebrafish cells

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2011-02-08 | E-GEOD-23872 | biostudies-arrayexpress