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Omics score: 27

Reprogramming Transcriptional Responses through Functionally-Distinct Classes of Enhancers in Prostate Cancer Cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series

OTHER RELATED OMICS DATASETS IN: PRJNA141877PRJNA137903E-GEOD-27823PRJNA141903

INSTRUMENT(S): Illumina human-6 v2.0 expression beadchip

SUBMITTER: Christopher Benner

PROVIDER: GSE27824 | GEO | 2011-05-15

SECONDARY ACCESSION(S): GSE27823 GSE27682PRJNA137903

REPOSITORIES: GEO

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Publications

Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.

Wang Dong D Garcia-Bassets Ivan I Benner Chris C Li Wenbo W Su Xue X Zhou Yiming Y Qiu Jinsong J Liu Wen W Kaikkonen Minna U MU Ohgi Kenneth A KA Glass Christopher K CK Rosenfeld Michael G MG Fu Xiang-Dong XD

Nature 20110515 7351

Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and fu ...[more]

PMID: 21572438

Similar Datasets

Reprogramming Transcriptional Responses through Functionally-Distinct Classes of Enhancers in Prostate Cancer Cells [gene expression]

Project description:Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell type-specific gene expression programs; however, the potential that there are pre-established enhancers in different functional classes that permit alternative signal-dependent transcriptional responses has remained unexplored. Here we present evidence that cell lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), acting at structurally- and functionally-distinct classes of pre-established enhancers, thus licensing specific signal-activated responses while restricting others. Consequently, FoxA1 down-regulation, an unfavorable prognostic sign in advanced prostate tumors, causes a massive switch in AR binding from one functional class of enhancers to another, with a parallel switch in levels of enhancer-templated non-coding RNAs (eRNAs) revealed by the global run-on assay (GRO-seq), which documents the dramatic reprogramming of the hormonal response. The molecular basis for this switch lies in the release of FoxA1-mediated restriction of AR binding to the new enhancer class with no apparent nucleosome remodeling, which is required for stimulating their eRNA transcription and/or enhancing enhancer:promoter looping and gene activation. Together, these findings reveal a large repository of pre-determined enhancers in the human genome that can be dynamically tuned to induce their transcription and activation of alternative gene expression programs, which may underlie many sequential gene expression events in development or during disease progression. ChIP-Seq, Gro-Seq, and gene expression profiling was performed in LNCaP cells with hormone treatment and siRNA against FoxA1. Gene expression profiling data presented here.

2011-05-15 | E-GEOD-27682 | ArrayExpress

Reprogramming Transcriptional Responses through Functionally-Distinct Classes of Enhancers in Prostate Cancer Cells [ChIP-Seq, Gro-Seq]

2011-05-15 | E-GEOD-27823 | ArrayExpress

Reprogramming Transcriptional Responses through Functionally-Distinct Classes of Enhancers in Prostate Cancer Cells

Project description:Reprogramming Transcriptional Responses through Functionally-Distinct Classes of Enhancers in Prostate Cancer Cells

| PRJNA137903 | ENA

Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA.

Project description:Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.

2011-01-01 | S-EPMC3117022 | BioStudies

Three functionally distinct classes of C-fibre nociceptors in primates.

Project description:In primates, C-fibre polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of ?-alanine, an MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to ?-alanine, and their response is only half that of QCs. Mechanically insensitive C-fibres (C-MIAs) are ?-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that ?-alanine and histamine activate distinct populations of capsaicin-responsive neurons in primate dorsal root ganglion. We suggest that histamine itch and capsaicin pain are peripherally encoded in C-MIAs, and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with ?-alanine responsive QC fibres likely corresponding to murine MrgprD-expressing, non-peptidergic nociceptive afferents.

2014-01-01 | S-EPMC4072246 | BioStudies

Epigenetic signatures distinguish multiple classes of enhancers with distinct cellular functions.

Project description:Epigenetic regulation of gene enhancer elements is important for establishing and maintaining the identity of cells. Gene enhancer elements are thought to exist in either active or poised states distinguishable by chromatin features, but a complete understanding of the regulation of enhancers is lacking. Here, by using mouse embryonic stem cells and their differentiated derivatives, as well as terminally differentiated cells, we report the coexistence of multiple, defined classes of enhancers that serve distinct cellular functions. Specifically, we found that active enhancers can be subclassified based on varying levels of H3K4me1, H3K27ac, and H3K36me3 and the pSer2/5 forms of RNA polymerase II. The abundance of these histone modifications positively correlates with the expression of associated genes and cellular functions consistent with the identity of the cell type. Poised enhancers can also be subclassified based on presence or absence of H3K27me3 and H3K9me3, conservation, genomic location, expression levels of associated genes, and predicted function of associated genes. These findings not only refine the repertoire of histone modifications at both active and poised gene enhancer elements but also raise the possibility that enhancers associated with distinct cellular functions are partitioned based on specific combinations of histone modifications.

2011-01-01 | S-EPMC3149494 | BioStudies

Analysis of regulatory network topology reveals functionally distinct classes of microRNAs.

Project description:MicroRNAs (miRNAs) negatively regulate the expression of target genes at the post-transcriptional level. Little is known about the crosstalk between miRNAs and transcription factors (TFs). Here we provide data suggesting that the interaction patterns between TFs and miRNAs can influence the biological functions of miRNAs. From this global survey, we find that a regulated feedback loop, in which two TFs regulate each other and one miRNA regulates both of the factors, is the most significantly overrepresented network motif. Mathematical modeling shows that the miRNA in this motif stabilizes the feedback loop to resist environmental perturbation, providing one mechanism to explain the robustness of developmental programs that is contributed by miRNAs. Furthermore, on the basis of a network motif profile analysis, we demonstrate the existence of two classes of miRNAs with distinct network topological properties. The first class of miRNAs is regulated by a large number of TFs, whereas the second is regulated by only a few TFs. The differential expression level of the two classes of miRNAs in embryonic developmental stages versus adult tissues suggests that the two classes may have fundamentally different biological functions. Our results demonstrate that the TFs and miRNAs extensively interact with each other and the biological functions of miRNAs may be wired in the regulatory network topology.

1000-01-01 | S-EPMC2582613 | BioStudies

Reprogramming identifies functionally distinct stages of clonal evolution in myelodysplastic syndromes.

Project description:Myeloid neoplasms, including myelodysplastic syndromes (MDS), are genetically heterogeneous disorders driven by clonal acquisition of somatic mutations in hematopoietic stem and progenitor cells (HPCs). The order of premalignant mutations and their impact on HPC self-renewal and differentiation remain poorly understood. We show that episomal reprogramming of MDS patient samples generates induced pluripotent stem cells from single premalignant cells with a partial complement of mutations, directly informing the temporal order of mutations in the individual patient. Reprogramming preferentially captured early subclones with fewer mutations, which were rare among single patient cells. To evaluate the functional impact of clonal evolution in individual patients, we differentiated isogenic MDS induced pluripotent stem cells harboring up to 4 successive clonal abnormalities recapitulating a progressive decrease in hematopoietic differentiation potential. SF3B1, in concert with epigenetic mutations, perturbed mitochondrial function leading to accumulation of damaged mitochondria during disease progression, resulting in apoptosis and ineffective erythropoiesis. Reprogramming also informed the order of premalignant mutations in patients with complex karyotype and identified 5q deletion as an early cytogenetic anomaly. The loss of chromosome 5q cooperated with TP53 mutations to perturb genome stability, promoting acquisition of structural and karyotypic abnormalities. Reprogramming thus enables molecular and functional interrogation of preleukemic clonal evolution, identifying mitochondrial function and chromosome stability as key pathways affected by acquisition of somatic mutations in MDS.

2019-01-01 | S-EPMC6624967 | BioStudies

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Project description:Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression.

2019-01-01 | S-EPMC6467783 | BioStudies

Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment.

Project description:Planarians are flatworms capable of regenerating any missing body region. This capacity is mediated by neoblasts, a proliferative cell population that contains pluripotent stem cells. Although population-based studies have revealed many neoblast characteristics, whether functionally distinct classes exist within this population is unclear. Here, we used high-dimensional single-cell transcriptional profiling from over a thousand individual neoblasts to directly compare gene expression fingerprints during homeostasis and regeneration. We identified two prominent neoblast classes that we named ? (zeta) and ? (sigma). Zeta-neoblasts encompass specified cells that give rise to an abundant postmitotic lineage, including epidermal cells, and are not required for regeneration. By contrast, sigma-neoblasts proliferate in response to injury, possess broad lineage capacity, and can give rise to zeta-neoblasts. These findings indicate that planarian neoblasts comprise two major and functionally distinct cellular compartments.

2014-01-01 | S-EPMC4171737 | BioStudies

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