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Chromatin opening by p53 is confined by Trim24 in a histone methylation-dependent manner [ATAC-seq]

ABSTRACT: Chromatin modifications are thought to provide additional context dependence for sequence-based gene activation. Binding sites of the transcription factor (TF) and important tumor suppressor p53 are unusually diverse with regards to their chromatin accessibility and histone modifications, suggesting different modes of binding. Here, we show that the ability of p53 to open chromatin and activate its target genes upon DNA damage is locally restricted by its cofactor Trim24. The histone-binding domains of Trim24 limit the role of p53 at closed chromatin but not at accessible chromatin where Trim24 is blocked by histone 3 methylation at lysine 4. In turn p53 regulates gene expression as a function of the naïve chromatin state prior to activation. These findings establish a set of p53 response genes in closed chromatin that are Trim24-regulated and illustrate how histone modification sensing cofactors bridge local chromatin state and TF potency.

ORGANISM(S): Mus musculus

PROVIDER: GSE200582 | GEO | 2023/04/30

REPOSITORIES: GEO

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Chromatin opening by p53 is confined by Trim24 in a histone methylation-dependent manner [RNA-seq]

Project description:Chromatin modifications are thought to provide additional context dependence for sequence-based gene activation. Binding sites of the transcription factor (TF) and important tumor suppressor p53 are unusually diverse with regards to their chromatin accessibility and histone modifications, suggesting different modes of binding. Here, we show that the ability of p53 to open chromatin and activate its target genes upon DNA damage is locally restricted by its cofactor Trim24. The histone-binding domains of Trim24 limit the role of p53 at closed chromatin but not at accessible chromatin where Trim24 is blocked by histone 3 methylation at lysine 4. In turn p53 regulates gene expression as a function of the naïve chromatin state prior to activation. These findings establish a set of p53 response genes in closed chromatin that are Trim24-regulated and illustrate how histone modification sensing cofactors bridge local chromatin state and TF potency.

2023-04-30 | GSE200581 | GEO

Chromatin opening by p53 is confined by Trim24 in a histone methylation-dependent manner [ChIP-seq]

2023-04-30 | GSE200580 | GEO

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53

Project description:The genomic binding sites of the transcription factor (TF) and tumour suppressor p53 are unusually diverse in regards to their chromatin features, including histone modifications, opening the possibility that chromatin provides context-dependence for p53 regulation. Here, we show that the ability of p53 to open chromatin and activate its target genes is indeed locally restricted by its cofactor Trim24. Trim24 binds to both p53 and unmethylated lysine 4 of histone H3, thereby preferentially locating to those p53 sites that reside in closed chromatin, while it is deterred from accessible chromatin by lysine 4 methylation. The presence of Trim24 increases cell viability upon stress and enables p53 to impact gene expression as a function of the local chromatin state. These findings link histone methylation to p53 function and illustrate how specificity in chromatin can be achieved, not by TF-intrinsic sensitivity to histone modifications, but by employing chromatin-sensitive cofactors which locally modulate TF function.

2023-05-05 | PXD039553 | Pride

Investigation upon the state of p53 as well as interaction partners, in so much as can be learned from using the multi-component v5-dTag system.

Project description:Chromatin modifications provide additional context-dependence for DNA sequence-based gene regulation. Binding sites of the transcription factor (TF) and important tumour suppressor p53 are unusually diverse with regards to their chromatin accessibility and histone modifications, suggesting different modes of binding. Here, we show that the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. The histone-binding domains of Trim24 limits the role of p53 at closed chromatin but not at accessible chromatin where Trim24 is blocked by histone 3 methylation at lysine 4. In turn, p53 regulates gene expression as a function of the naïve chromatin state prior to activation. These findings establish a novel mode of gene regulation by p53 in closed chromatin and illustrate how histone modification sensing cofactors can bridge local chromatin state and TF potency.

2023-05-05 | PXD033674 | Pride

Cyclic LSD1 recruitment and dynamic H3K4 methylation establish TRIM24-activated estrogen response

Project description:The role of histone lysine methylation in estrogen receptor-alpha (ERα)-activated transcription is highly context-specific and poorly understood. Here, we show that lysine demethylase 1 (LSD1) mediates loss of H3 lysine 4 dimethylation (H3K4me2) in coordination with tripartite-motif-containing protein 24 (TRIM24)- regulated growth of breaset cancer-derived cells. We performed global profiling of histone H3K4me2 in comparison to genome-wide binding of TRIM24 in MCF7 cells when estrogen is depleted or added. We found specific subsets of genes with functions in transcription and cell proliferation are depleted of H3K4me2 at TRIM24 binding sites. Chromatin immunoprecipitation (ChIP) analyses over a time course of estrogen induction revealed cyclic demethylation of H3K4me2, LSD1, TRIM24 and ERα binding. Inhibition of LSD1 enzymatic activity led to increased H3K4me2 and decreased estrogen response of TRIM24-dependent genes. Additon of a small molecule inhibitor of the TRIM24 bromodomain or depletion of TRIM24 expression amplified the impact of LSD1 inhbition as measured by survival and proliferation of MCF7 cells, suggesting that combinatorial inhibition of LSD1 and TRIM24 may be effective in targeting ER-positive breast cancers.

2019-12-01 | GSE113654 | GEO

Stat6 occupancy profiling by high throughput sequencing from wild-type(WT) or Trim24-deficient(Trim24-KO) mouse peritoneal macrophages stimulated with IL-4 for 1 hour .

Project description:To identify the potential genes that regulated by Trim24 through Stat6 DNA binding activity, we immunoprecipitated chromatin from WT or Trim24-KO macrophages stimulated with IL-4, and analyzed the precipitated DNA with deep sequencing (ChIP-Seq).

2019-09-06 | GSE134167 | GEO

Trim24 knock down in the 2i-state of the mouse ES cells

Project description:Differentially expressed genes were determined by single-end sequencing (stranded protocol) following Trim24 and/or p53 knock down in the mouse ES cells grown in 2i media. Triplicates were generated for treatment and control samples but for p53 knock down (duplicate).

2017-11-08 | E-MTAB-4893 | biostudies-arrayexpress

Chromatin enrichment of TRIM24, estrogen receptor and H3K4me2 in estrogen-treated and -untreated MCF7 cells

Project description:TRIM24 PHD-Bromo domains exhibit preferential binding to unmethylated H3K4 and acetylated H3K27. TRIM24 is a co-activator of estrogen receptor (ER). The results suggest that specific ER-binding sites are depleted of H3K4me2 with estrogen treatment. TRIM24 binds these sites preferentially and facilitates ER-regulated gene expression, cell survival and proliferation. ChIP performed on MCF7 cells +/- estrogen with antibodies against ER, TRIM24 and H3K4me2. ChIP assays of ER, co-activator TRIM24 and H3K4me2 were performed with two concentrations of antibody, without and 6h with estrogen treatment of MCF7 cells. Antibody-enriched samples were sequenced two times, and compared to an IgG negative control and Input. Enriched DNA sequenced by Illumina Solexa.

2010-09-17 | E-GEOD-24166 | biostudies-arrayexpress

Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer and nominates c-Met and TRIM24 as therapeutic targets

Project description:Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature revealed strong correlation with human MpBC tumors and MpBC xenograft (PDX) models. Global and single-cell tumor profiling revealed Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC PDX tumorspheres revealed the therapeutic potential of targeting TRIM24. Altogether, global expression, single-cell immunophenotyping and mechanistic studies of tumors and MpBC PDX nominated TRIM24-activated c-MET/PI3K/mTOR pathways and TRIM24, which were validated as potential MpBC therapeutic targets.

2021-06-25 | GSE165407 | GEO

Chromatin enrichment of TRIM24, estrogen receptor and H3K4me2 in estrogen-treated and -untreated MCF7 cells

2010-09-17 | GSE24166 | GEO

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