Similar Datasets
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE118218 | GEO
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE124582 | GEO
Project description:Silencing of the somatic cell-type specific gene expression programs is a critical yet poorly understood step in nuclear reprogramming. To uncover chromatin-related pathways important for maintaining cell identity, we carried out a reprogramming screen using inhibitors of chromatin factors. Here we identify two independent acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators EP300 and CBP as potent enhancers of reprogramming. EP300/CBP bromodomain inhibition is critical during early stages of reprogramming, significantly accelerates the emergence of iPSCs and, when combined with Dot1L inhibition, enables efficient derivation of human iPSCs with Oct4 and Sox2 alone. In contrast, complete inhibition of catalytic acetyl-transferase activity of EP300/CBP prevents reprogramming. Genome-wide expression analyses indicate that EP300/CBP bromodomain inhibition diminishes the expression of somatic-specific genes without affecting the induction of pluripotency regulators. Through expression analyses, we identify the master mesenchymal transcription factor PRRX1 as a functionally important target in reprogramming that is downregulated upon EP300/CBP bromodomain inhibition. Collectively, our data uncover a role for bromodomain-mediated interactions of EP300/CBP in sustaining cell type specific gene expression programs and maintaining somatic cell identity
2019-02-14 | GSE124581 | GEO
Project description:Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
| S-EPMC6504645 | biostudies-literature
Project description:Bromodomain inhibition of the co-activators CBP/EP300 facilitates reprogramming
| PRJNA484883 | ENA
Project description:Bromodomain inhibition of the co-activators CBP/EP300 facilitates reprogramming (ATAC-seq)
| PRJNA484886 | ENA
Project description:Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.
| S-EPMC4933219 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-04-08 | GSE70709 | GEO
Project description:Bromodomain inhibition of the co-activators CBP/EP300 facilitates reprogramming (ChIP-seq II)
| PRJNA512535 | ENA
Project description:Bromodomain inhibition of the co-activators CBP/EP300 facilitates reprogramming (RNA-seq fibroblasts)
| PRJNA512532 | ENA