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Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells

ABSTRACT: MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here a new map of the transcriptional regulatory circuitry of ES cells that incorporates both protein-coding and miRNA genes, and which is based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for most miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb Group proteins in ES cells and expressed in a tissue-specific fashion in differentiated cells. These data reveal how key ES cell transcription factors promote the miRNA expression program that contributes to self-renewal and cellular differentiation, and integrate miRNAs and their targets into an expanded model of the regulatory circuitry controlling ES cell identity. Keywords: ChIP-seq analysis of ES cell transcriptional regulators and chromatin modifications. Cell-type comparison of short RNA transcritome. Analysis of changes in short RNA transcritome upon Oct4 ablation.

ORGANISM(S): Mus musculus

PROVIDER: GSE11724 | GEO | 2008/07/30

SECONDARY ACCESSION(S): PRJNA106023

REPOSITORIES: GEO

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Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells

Project description:MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here a new map of the transcriptional regulatory circuitry of ES cells that incorporates both protein-coding and miRNA genes, and which is based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for most miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb Group proteins in ES cells and expressed in a tissue-specific fashion in differentiated cells. These data reveal how key ES cell transcription factors promote the miRNA expression program that contributes to self-renewal and cellular differentiation, and integrate miRNAs and their targets into an expanded model of the regulatory circuitry controlling ES cell identity. Keywords: ChIP-seq analysis of ES cell transcriptional regulators and chromatin modifications. Cell-type comparison of short RNA transcritome. Analysis of changes in short RNA transcritome upon Oct4 ablation. ChIP-seq in murine embryonic stem cells for Oct4, Sox2 (2 runs), Nanog (2 runs), Tcf3 (2 runs), Suz12 (2 runs), H3K4me3 (4 runs), H3k79me2 (2 runs), H3k36me3 (2 runs) and whole cell extract input DNA (WCE, 2 runs). Short transcript sequencing from murine embryonic stem cells (mES, v6.5), mouse embryonic fibroblasts (MEF), murine neural precursor cells (NPC), and ZHBT-c4 cells (from Austin Smith) untreated (0h), with 12 hours of doxycyclin treatment (12h), and with 24 hours of doxycyclin treatment (24h).

2008-07-29 | E-GEOD-11724 | biostudies-arrayexpress

Chromatin immunoprecipitation of Oct4, Nanog and Suz12 in human and mouse embryonic stem cells to identify promoters for miRNAs

Project description:Understanding the transcriptional regulatory circuitry responsible for pluripotency and self-renewal in embryonic stem (ES) cells is fundamental to understanding human development and realizing the therapeutic potential of these cells. The transcription factor Oct4 and the chromatin-modifying Polycomb complex, key regulators of ES cell pluripotency and self-renewal, contribute to positive and negative control of a known set of protein-coding genes. MicroRNAs (miRNAs), non-coding transcripts that participate in post-transcriptional gene regulation are also important for normal pluripotency and self-renewal in ES cells, but there has been no systematic investigation of how miRNA expression is controlled by transcriptional regulators of ES cell identity. Here we identify promoters for miRNAs in the human and mouse genomes and describe the subset of these genes that are under the control of Oct4 and Polycomb in ES cells. We find that the majority of miRNAs that are uniquely or preferentially expressed in ES cells are bound by and dependent on Oct4. Oct4 also occupies a set of miRNA genes that are co-occupied by the Polycomb Group protein, Suz12. These miRNAs, repressed in ES cells, are later expressed in differentiated cells in a highly tissue-specific fashion, suggesting that they may contribute to cell-fate determinations. These data reveal how the core transcriptional regulatory circuitry of ES cells controls the miRNA expression program that contributes to pluripotency and self-renewal.

2010-12-01 | E-TABM-365 | biostudies-arrayexpress

Esrrb Regulates Specific Feed-Forward Loops to Transit from Pluripotency into Early Stages of Differentiation

Project description:Characterization of pluripotent states, in which cells can both self-renew or differentiate, with the irreversible loss of pluripotency, are important research areas in developmental biology. Although microRNAs (miRNAs) have been shown to be crucial for embryonic stem (ES) self-renewal maintenance and cellular differentiation, the role of miRNAs integrated into gene regulatory networks and its dynamic changes during these state transitions remain elusive. Here we describe the dynamic transcriptional regulatory circuitry of ES cells that incorporate protein-coding and miRNA genes based on microRNA array expression and quantitative sequencing of short transcripts upon the downregulation of the Estrogen Related Receptor Beta (Esrrb). The data reveals how Esrrb, a key stem cell transcription factor, regulates a specific ES cell miRNA expression program and integrates dynamic changes of feed forward loops contributing to the exit of the pluripotency state upon its downregulation. Together these findings provide new insights on the architecture of the combined transcriptional post-transcriptional regulatory network in stem cells.

2022-03-21 | GSE57371 | GEO

Esrrb Regulates Specific Feed-Forward Loops to Transit from Pluripotency into Early Stages of Differentiation (RNA-Seq)

2022-03-21 | GSE189678 | GEO

An integrated expression atlas of miRNAs and their promoters in human and mouse

Project description:MicroRNAs (miRNAs) are short non-coding RNAs with key roles in cellular regulation. We created the first integrated expression atlas of miRNAs and their promoters in mammalian cells by deep sequencing matched short RNA (sRNA) and Cap Analysis Gene Expression (CAGE) libraries from 492 RNA samples. Most samples were derived from human primary cells, allowing us to annotate each human miRNA by its sRNA expression profile across primary cell types. Promoters were identified for 1,357 human and 804 mouse miRNAs and showed strong sequence conservation between species, reflecting the importance of transcriptional regulation of miRNA expression. As primary and mature miRNA expression levels in the matched libraries were correlated, CAGE expression of primary miRNAs could be used as a proxy for the expression level of mature miRNAs, allowing us to extend the miRNA expression survey to the 1,829 human and 1,029 mouse CAGE libraries in FANTOM5. We thus provide the first broad atlas of miRNA expression in primary cells, as well as the largest map of miRNA promoters to date, establishing the foundation for detailed analysis of expression patterns and transcriptional control regions of miRNAs.

2017-08-16 | GSE98695 | GEO

Sumoylated hnrnpa2b1 controls the sorting of miRNAs into two exosomes through binding to specific motifs

Project description:Exosomes are released by most cells to the extracellular environment, and are involved in cell-to-cell-communication. Exosomes contain specific repertoires of mRNAs, miRNAs and other non-coding RNAs that can be functionally transferred to recipient cells. However, the mechanisms that control the specific loading of RNA species into exosomes remain unknown. Here we describe short sequence motifs present in miRNAs that control their localization into exosomes. The protein hnRNPA2B1 specifically binds exosomal miRNAs through the recognition of these motifs and controls their loading into exosomes. Moreover, hnRNPA2B1 in exosomes is sumoylated, and sumoylation controls the binding of hnRNPA2B1 to miRNAs. The loading of miRNAs into exosomes can be modulated by mutagenesis of the identified motifs or changes in hnRNPA2B1 expression levels. These findings identify hnRNPA2B1 as a key player in miRNA sorting into exosomes and provide potential tools for the packaging of selected regulatory RNAs into exosomes and their use in biomedical applications.

2014-04-16 | PXD000350 | Pride

Identification of functional miRNA gene interactions in mESC by computational data integration approaches.

Project description:miRNAs are short regulatory single stranded RNA sequences that upon complementary binding to mRNAs lead to the inhibition or degradation of their targets. This regulatory mechanisms has been shown to play crucial roles throughout the whole life cycle of animals and plants as well as in disease. While a plethora of methods exist to predict targets of miRNA, which suggest that up to 80% of the genome is miRNA regulated, it has recently been reported that many of these predictions are false positives, cell type specific or represent non-functional binding. In order to identify the subset of real functional miRNAs and their targets, we established miRNA pathway mutants in mouse embryonic stem cells (mESC), allowing the dissection of canonical and non-canonical functions of pathway members. Additional data integration of downstream regulatory layers (CLIP-seq, ribosome profiling and MS) enabled us to follow and track down real functional miRNA-gene interactions, which reduced the miRNA genome regulation to approximately 1%.

2022-08-31 | PXD014484 | Pride

A quantitative map of human primary microRNA processing sites

Project description:Maturation of canonical microRNA (miRNA) is initiated by DROSHA that cleaves the primary transcript (pri-miRNA). Over 1,800 miRNA loci are annotated in humans, but it remains largely unknown if and at which sites the pri-miRNAs are cleaved by DROSHA. Here we performed in vitro processing on a full set of human pri-miRNAs (miRBase v21) followed by sequencing. This comprehensive profiling enabled us to classify miRNAs based on DROSHA-dependence and map their cleavage sites with respective processing efficiency measures. Only 758 pri-miRNAs are confidently processed by DROSHA, while the majority may be non-canonical or false entries. Analyses of the DROSHA-dependent pri-miRNAs show key cis-elements for processing. We observe widespread alternative processing as well as unproductive cleavage events such as “nick” or “inverse” processing. SRSF3 is a broad-acting auxiliary factor modulating alternative processing and suppressing unproductive processing. The profiling data and methods developed in this study will allow systematic analyses of miRNA regulation.

2021-07-28 | PXD025767 | Pride

The Interplay between K63-linked Polyubiquitinated DDX17 and m6A-modified miRNAs Regulates Hypoxia-induced Tumor Initiation

Project description:DEAD-box RNA-binding proteins (RBPs) play a significant role in RNA metabolism to achieve cellular homeostasis, including miRNA biogenesis and transcription. Hypoxia induces stemness cell-like characteristics in cancer cells and promotes malignant progression. Despite the fact that hypoxia can induce the changes in protein and RNA modification, thereby regulating downstream gene expressions, how modifications at different molecular layers interplay with each other are poorly understood. Here we show that hypoxia induces HectH9-mediated K63-linked polyubiquitination of the DEAD-box protein DDX17 as well as reduces N6-methyladenosine (m6A) marks in pri-miRNAs. While m6A potentiates DDX17 binding to pri-miRNAs, decreased m6A modifications of pri-miRNAs and increased polyubiquitination of DDX17 under hypoxia lead to decreased DDX17 binding to pri-miRNAs binding. These events enhance the association of DDX17 with the ubiquitin receptor p300 and lead to a decrease in miRNA biogenesis, especially for miRNAs regulating stemness and stemness-related genes. In addition, polyubiquitinated DDX17 together with p300 upregulates H3K56Ac levels on the stemness and stemness-related genes, resulting in enhancement of tumor initiating ability. Post-transcriptionally, decreased miRNA production, including those targeting stemness genes or stemness-related genes, also facilitates tumor initiation. Together, hypoxia triggers DDX17 poly-ubiquitination, which orchestrates dual mechanisms to increase tumor initiating ability and promote tumor progression.

2018-03-09 | PXD006059 | JPOST Repository

Chromatin immunoprecipitation of Tcf3, Oct4 and nanog in mouse embryonic stem cells

Project description:Embryonic stem cells have a unique regulatory circuitry, largely controlled by the transcription factors Oct4, Sox2 and Nanog, which generates a gene expression program necessary for pluripotency and self-renewal (Boyer et al. 2005; Loh et al. 2006; Chambers et al. 2003; Mitsui et al. 2003; Nichols et al. 1998). How external signals connect to this regulatory circuitry to influence embryonic stem cell fate is not known. We report here that a terminal component of the canonical Wnt pathway in embryonic stem cells, the transcription factor Tcf3, co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog. Thus Tcf3 is an integral component of the core regulatory circuitry of ES cells, which includes an autoregulatory loop involving the pluripotency regulators. Both Tcf3 depletion and Wnt pathway activation cause increased expression of Oct4, Nanog and other pluripotency factors and enhance pluripotency and self-renewal. Our results reveal that the Wnt pathway, through Tcf3, brings developmental signals directly to the core regulatory circuitry of ES cells to influence the balance between pluripotency and differentiation.

2008-02-28 | E-TABM-409 | biostudies-arrayexpress

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