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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113654 | GEO | 2019/12/01

REPOSITORIES: GEO

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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

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

2010-09-17 | GSE24166 | GEO

Cancer-associated E239K mutation of LSD1 promotes the migration and invasion of luminal breast cancer cells by reducing the expression of ERα

Project description:Background: Epithelial to mesenchymal transition (EMT) plays an essential role in the metastasis of breast cancer by regulating the migration and invasion of cancer cells. Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates EMT. However, the functional effects of the mutation on LSD1 in breast cancer remain unclear. Results: An E239K mutation of LSD1 was identified from TCGA Breast Invasive Carcinoma cohort. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with the wild-type LSD1, but not the E239K mutated LSD1, suppressed the increased invasion of the LSD1 knockdown cells, demonstrating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion of breast cancer cells. Further analysis showed that the E239K mutation of LSD1 led to decreased expression of estrogen receptor α (ERα), which subsequently increased the expression of Slug, a master transcription factor that promoted EMT. Most importantly, the E239K mutation of LSD1 disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of ERα gene. The reduced enrichment of LSD1 at the promoter region of ERα gene caused enhanced histone H3K9 methylation, which in turn suppressed the transcription of ERα gene. Conclusions: The E239K mutation of LSD1 promotes the migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3, which reduces the expression of ERα by enhancing the histone H3K9 methylation.

2021-03-12 | GSE168706 | GEO

Genome-wide map of lysine specific demethylase 1 (LSD1) in mouse embryonic stem cells.

Project description:We report the identification of LSD1 binding genomic regions in mouse embryonic stem cells (ESC) by high throughput sequencing. By obtaining over 10 million 36 bp reads of sequence from each chromatin immunoprecipitated DNA, we generated genome-wide maps for LSD1 and histone H3 dimethylated on lysine 4 (H3K4me2), the substrate for LSD1 in mouse ESCs. Our results showed an extensive overlap between the LSD1 and H3K4me2 genomic regions and a correlation between the genomic levels of LSD1/H3K4me2 and gene expression, including many highly expressed ESC genes. LSD1 is recruited to the chromatin of cells in the G1/S/G2 phases and is displaced from the chromatin of M phase cells, suggesting that LSD1 or H3K4me2 alternatively occupies LSD1 genomic regions during cell cycle progression. LSD1 knockdown by RNA interference or its displacement from the chromatin by anti-neoplastic agents caused an increase in the levels of a subset of LSD1 target genes. Taken together, these results suggest that cell-cycle dependent association and dissociation of LSD1 with chromatin mediates short-time scale gene expression changes during ES cell cycle progression. Examination of LSD1 and lysine 4 dimethylated histone H3 (H3K4me2) binding genomic regions in embryonic stem cells. Input genomic DNA and DNA immunoprecipitaed with control IgG was included as controls.

2012-10-03 | E-GEOD-18515 | biostudies-arrayexpress

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Project description:ERα is essential for the anti-proliferative response of breast cancer cells not only to estrogen antagonists, but also to estrogen withdrawal by means of aromatase inhibitors. We explored here one of the simplest explanation for this, consisting in the possibility that ERα may have a wide genomic function in absence of ligands. The genomic binding of ERα in the complete absence of estrogen was then studied using hormone-dependent MCF7 cells, by chromatin immunoprecipitation sequencing. From these data, 4.2K highly significant binding events were identified, which were further confirmed by comparing binding events in cells expressing ERα to cells silenced for ERα. Apo-ERα binding sites were distributed close to genes with functions associated to cell growth and epithelial maintenance and show significant overlap with binding of other transcription factors important for luminal epithelial breast cancer. Interestingly, we found that upon ERα silencing cognate gene transcription in absence of estrogen is downregulated and this is accompanied by increased H27Kme3 at ERα binding sites. RNA-Seq experiments showed that unliganded ERα controls basal transcription widely, including both coding and noncoding transcripts. Genes affected by ERα silencing can be easily functionally related to mammary epithelium differentiation and maintenance, especially when considering downregulated genes. Additional functions related to inflammatory and immune response was observed. Our data unravel unexpected actions of ERα in breast cancer cells and provide a novel framework to understand success and failure of hormone therapy in breast cancer. Examination of unligandend estrogen receptor alpha (aERα) DNA interactions in control and aERα siRNA treated MCF7 cells.

2014-03-03 | E-GEOD-53532 | biostudies-arrayexpress

H4K12ac is regulated by estrogen receptor-alpha and is associated with BRD4 function and inducible transcription

Project description:Hormone-dependent gene expression requires dynamic and coordinated epigenetic changes. Estrogen receptor-positive (ER+) breast cancer is particularly dependent upon extensive chromatin remodeling and changes in histone modifications for the induction of hormone-responsive gene expression. Our previous studies established an important role of bromodomain-containing protein-4 (BRD4) in promoting estrogen-regulated transcription and proliferation of ER+ breast cancer cells. Here, we investigated the association between genome-wide occupancy of histone H4 acetylation at lysine 12 (H4K12ac) and BRD4 in the context of estrogen-induced transcription. Similar to BRD4, we observed that H4K12ac occupancy increases near the transcription start sites (TSS) of estrogen-induced genes as well as at distal ERα binding sites in an estrogen-dependent manner. Interestingly, H4K12ac occupancy highly correlates with BRD4 binding and enhancer RNA production on ERα-positive enhancers. Consistent with an importance in estrogen-induced gene transcription, H4K12ac occupancy globally increased in ER-positive cells relative to ER-negative cells and these levels were further increased by estrogen treatment in an ERα-dependent manner. Together, these findings reveal a strong correlation between H4K12ac and BRD4 occupancy with estrogen-dependent gene transcription and further suggest that modulators of H4K12ac and BRD4 may serve as new therapeutic targets for hormone-dependent cancers. ChIP-seq profiles of H4K12ac in MCF7 cells treated with +/- estrogen treatment and MCF10A cells.

2015-05-02 | E-GEOD-65886 | biostudies-arrayexpress

Homo sapiens

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

| PRJNA130083 | ENA

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2020-09-02 | PXD018709 | Pride

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Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies that although effective can generate resistance phenomena that represents a crucial problem in clinical management of patients affected by this disease. DOT1 Like Histone Lysine Methyltransferase (DOT1L) and Menin 1 (MEN1) have been identified as functional component of the ERα mechanism of action. To investigate the involvement of DOT1L and MEN1 in mediating ERα actions in hormone-responsive and endocrine-resistant BC, interaction proteomics was applied to map the DOT1l and MEN1 nuclear interacting partners in MCF7 breast cancer cell nuclei in order to the identifiy new possible therapeutic targets for a more effective pharmacological treatment of endocrine therapy-resistant tumors.

2022-08-12 | PXD026864 | Pride

ChIP-chip of siGFP- or siHOTAIR-treated foreskin fibroblasts with anti-H3K4me2, anti-LSD1 or anti-SUZ12 antibodies on HOX tiling array

Project description:Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5’ domain of HOTAIR binds Polycomb Repressive Complex 2 (PRC2) while a 3’ domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1, and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, and thereby specify the pattern of histone modifications on target genes. Coordinate loss of SUZ12 and LSD1 occupancy caused by HOTAIR knockdown were concentrated in proximal promoters of HOXD genes. These regions correspondingly lost H3K27me3 and gained H3K4me2, the respective histone methylation products of PRC2 and LSD1 complexes. Comparison occupancy of LSD1 and SUZ12 of siGFP and siHOTAIR foreskin fibroblasts on HOX tiling array. Human foreskin fibroblasts were transfected with siGFP or siHOTAIR. The cells were harvested and ChIP analysis with anti-H3K4me2, anti-LSD1 and anti-SUZ12 antibodies was performed.

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