Characterizing heterogeneous cis-regulatory elements in gene regulatory programs associated with breast cancer
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PROVIDER: PRJNA1274379 | ENA |
REPOSITORIES: ENA
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Project description:Background: Cis-regulatory elements (CREs) control oncogene expression and malignant phenotypes. The high clinicopathological heterogeneity of cancer cannot be explained by gene expression alone, being attributed to CRE heterogeneity. However, characterizing cancer-associated CRE is challenging. To address this issue, we performed a single-cell epigenomic analysis of clinical specimens. Methods: To map the multicellular ecosystem of BC and identify candidate CREs (cCREs), we performed a single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq) of 38 prospectively collected breast cancer (BC) samples with various clinicopathological characteristics. Results: First, we performed single-cell chromatin accessibility profiling of a high-quality set of 22,775 cells from BC samples. Cells were accurately annotated using marker gene accessibility and integration with existing single-cell RNA sequencing data. By predicting copy number variants, epithelial cells were classified into non-malignant and malignant cells. The chromatin accessibility patterns exhibited by malignant cells were consistent with the clinicopathological features of each tumor. We identified 224,585 cCREs across the BC ecosystem. By identifying cluster-specific differentially accessible cCREs (DA-cCREs) and constructing a putative enhancer-promoter network, we mapped the cis-regulatory landscape for cancer cells and the tumor microenvironment. In this dataset, we identified changes in the cis-regulatory landscape associated with cancer progression. In particular, estrogen receptor (ER)-positive tumors have increased accessibility of ER binding motifs during the cell transition from non-cancerous to cancerous and increased accessibility of Kruppel like factor motifs during the transition from cancerous to metastatic. Furthermore, the accessibility of putative enhancers targeting the same gene differed within or between tumors, highlighting intra- and inter-cis-regulatory tumor heterogeneity. Conclusions: This study provides a valuable resource for future epigenetic research on BC and highlights the diverse regulatory landscape within or among tumor(s), suggesting that cCREs regulate tumor progression and intra- and inter-tumor heterogeneity.
2025-06-25 | GSE299408 | GEO
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Project description:The goal of this study is to improve the quality, efficiency, and sustainability of milk production by improving the understanding of the function of cis-regulatory elements in regulating the bovine mammary gland. To this end, we have characterized the non-lactating and lactating mammary gland transcriptomes by whole transcriptome shotgun sequencing (RNA-seq). We will identify cis-regulatory elements in the non-lactating and lactating bovine mammary gland genome-wide. Finally, we will annotate and characterize mammary gland cis-regulatory elements by computational analysis and identify high-resolution genome-wide in vivo footprints of diverse trans-acting-factors (TF), over-represented TF bindings sites and overlapping SNPs.
2021-04-06 | GSE116079 | GEO
Project description:Background Genomic variations contribute to the phenotypic diversity of individuals. A number of polymorphisms in protein-coding regions that alter drug efficacy or lead to adverse reactions have been characterized; however, noncoding regions that affect drug responses are largely overlooked, except for a limited number of well-studied enhancers. Results We conducted a quantitative assessment of cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) were further narrowed down by integrating data of PXR-binding sites in human primary hepatocytes and genome-wide association studies. We found more than 100-fold enrichments of the candidates to genetically associated loci with circulating levels of bilirubin and vitamin D, which implicated a link to adverse reactions of PXR ligands. We uncovered novel enhancers of UGT1A1 and TSKU through CRISPR/Cas9 knockout experiments. We identified alleles altering regulatory activities of UGT1A1 and CYP24A1enhancers by using luciferase reporter assay. Furthermore, our siRNA experiments revealed an unexpected impact of TSKU on the expression of vitamin D-metabolizing enzymes. Conclusions Our transcriptome-based assessment of CREs expanded the list of drug-inducible and PXR-mediated enhancers and super-enhancers. We identified regulatory alleles that alter drug-induced gene expressions, and discovered a novel molecular cascade associated with an adverse reaction. Our results contribute a precise understanding of the noncoding elements of the human genome underlying drug responses.
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Project description:Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. Here, we discovered that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscape critical for functional Treg cell differentiation.
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Project description:Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. Here, we discovered that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscape critical for functional Treg cell differentiation.
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Project description:Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. Here, we discovered that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscape critical for functional Treg cell differentiation.
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Project description:Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. Here, we discovered that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscape critical for functional Treg cell differentiation.
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Project description:Promoters and enhancers are key cis-regulatory elements, but how they operate to generate cell-type-specific transcriptomes is not fully understood. We developed a simple and robust approach to sensitively detect 5’-ends of nascent RNAs (NET-CAGE) in diverse cells and tissues, including unstable transcripts such as enhancer-derived RNAs. We studied RNA synthesis and degradation at the transcription start site (TSS) level, characterizing the impact of differential promoter usage on transcript stability. We quantified transcription from cis-regulatory elements without the influence of RNA turnover, and show that enhancer-promoter pairs are generally activated simultaneously upon stimulation. By integrating NET-CAGE data with chromatin interaction maps, we show that cis-regulatory elements are topologically connected according to their cell-type specificity. We identified new enhancers with high sensitivity, and delineated primary locations of transcription within super-enhancers. Our NET-CAGE dataset derived from human and mouse cells expands the FANTOM5 catalogue of transcribed enhancers, with broad applicability to biomedical research.
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Project description:Mechanisms by which diverse transcription factors (TFs), particularly the master regulator Foxp3, shape the heterogeneous transcriptional and epigenetic landscape of regulatory T (Treg) cells remain poorly understood. Here, we discovered that Foxp3 cooperates with BATF to direct cis-regulatory programs and gene expression essential for differentiation of immunosuppressive effector Treg (eTreg) cells. Simultaneous single-cell chromatin accessibility and transcriptome profiling, combined with topic modeling, identified cis-regulatory elements and associated programs jointly regulated by these TFs in eTreg cells. Genome-wide mapping of Treg cell-specific BATF and eTreg cell-specific Foxp3 binding sites revealed their co-binding at some of these cis-elements, synergistically enhancing accessibility and transcription. Furthermore, we provide evidence that Foxp3 interacts with specific TFs to orchestrate diverse cis-regulatory programs among Treg cell differentiation states. Thus, Foxp3 serves as a master, but context-dependent regulator, cooperating with other TFs, including BATF, to shape the heterogeneous cis-regulatory and transcriptional landscape critical for functional Treg cell differentiation.
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