DDX5-deficiency affects cell fate decisions by regulating lineage specific genes and polycomb repressive complexes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76825 | GEO | 2017/01/22
SECONDARY ACCESSION(S): PRJNA308720
REPOSITORIES: GEO
Similar Datasets
Project description:RNA-binding proteins (RBPs) are involved in a wide variety of regulatory pathways in mammalian cells. Here, we report that the DEAD-box RBP DDX5 (also known as p68) inhibits induced pluripotency by negatively regulating the expression and function of a non-canonical polycomb complex 1 (PRC1) subunit, RYBP, by modulating microRNA-125b processing. DDX5 loss-of-function, both during reprogramming and the somatic to pluripotent transition, and also in the differentiation of mouse embryonic stem cells, results in the suppression of lineage-specific genes via an RYBP-dependent ubiquitination of histone H2A at K119 (H2AK119ub1). RYBP functions as both transcriptional repressor through PRC1 but also as an activator through its interaction with OCT4 during reprogramming. Diminished DDX5 also potentiates RYBP-mediated recruitment of OCT4 to the promoter of the pluripotency activation gene Kdm2b. These data show that DDX5 down-regulation stimulates silencing of lineage-specific genes by RYBP-PRC1 in the early phase of reprogramming and activation of the pluripotency gene network by RYBP-OCT4 in the later phase of reprogramming.
2017-01-22 | GSE76823 | GEO
Project description:DDX5-deficiency affects cell fate decisions by regulating lineage specific genes and polycomb repressive complexes
| PRJNA308720 | ENA
Project description:RNA-binding proteins (RBPs) are involved in a wide variety of regulatory pathways in mammalian cells. Here, we report that the DEAD-box RBP DDX5 (also known as p68) inhibits induced pluripotency by negatively regulating the expression and function of a non-canonical polycomb complex 1 (PRC1) subunit, RYBP, by modulating microRNA-125b processing. DDX5 loss-of-function, both during reprogramming and the somatic to pluripotent transition, and also in the differentiation of mouse embryonic stem cells, results in the suppression of lineage-specific genes via an RYBP-dependent ubiquitination of histone H2A at K119 (H2AK119ub1). RYBP functions as both transcriptional repressor through PRC1 but also as an activator through its interaction with OCT4 during reprogramming. Diminished DDX5 also potentiates RYBP-mediated recruitment of OCT4 to the promoter of the pluripotency activation gene Kdm2b. These data show that DDX5 down-regulation stimulates silencing of lineage-specific genes by RYBP-PRC1 in the early phase of reprogramming and activation of the pluripotency gene network by RYBP-OCT4 in the later phase of reprogramming.
2017-01-22 | GSE89690 | GEO
Project description:RNA-binding proteins (RBPs) are involved in a wide variety of regulatory pathways in mammalian cells. Here, we report that the DEAD-box RBP DDX5 (also known as p68) inhibits induced pluripotency by negatively regulating the expression and function of a non-canonical polycomb complex 1 (PRC1) subunit, RYBP, by modulating microRNA-125b processing. DDX5 loss-of-function, both during reprogramming and the somatic to pluripotent transition, and also in the differentiation of mouse embryonic stem cells, results in the suppression of lineage-specific genes via an RYBP-dependent ubiquitination of histone H2A at K119 (H2AK119ub1). RYBP functions as both transcriptional repressor through PRC1 but also as an activator through its interaction with OCT4 during reprogramming. Diminished DDX5 also potentiates RYBP-mediated recruitment of OCT4 to the promoter of the pluripotency activation gene Kdm2b. These data show that DDX5 down-regulation stimulates silencing of lineage-specific genes by RYBP-PRC1 in the early phase of reprogramming and activation of the pluripotency gene network by RYBP-OCT4 in the later phase of reprogramming.
2017-01-22 | GSE76824 | GEO
Project description:The polycomb group (PcG) proteins are a large and diverse family that epigenetically repress the transcription of key developmental genes. They form three broad groups of polycomb repressive complexes (PRCs) known as PRC1, PRC2 and Polycomb Repressive DeUBiquitinase, each of which modifies and/or remodels chromatin by distinct mechanisms that are tuned by having variable compositions of core and accessory subunits. Until recently, relatively little was known about how the various PcG proteins assemble to form the PRCs; however, studies by several groups have now allowed us to start piecing together the PcG puzzle. Here, we discuss some highlights of recent PcG structures and the insights they have given us into how these complexes regulate transcription through chromatin.
| S-EPMC5310723 | biostudies-literature
Project description:The polycomb group (PcG) proteins are a subset of transcription regulators highly conserved throughout evolution. Their principal role is to epigenetically modify chromatin landscapes and control the expression of master transcriptional programs to determine cellular identity. The two mayor PcG protein complexes that have been identified in mammals to date are Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2). These protein complexes selectively repress gene expression via the induction of covalent post-translational histone modifications, promoting chromatin structure stabilization. PRC2 catalyzes the histone H3 methylation at lysine 27 (H3K27me1/2/3), inducing heterochromatin structures. This activity is controlled by the formation of a multi-subunit complex, which includes enhancer of zeste (EZH2), embryonic ectoderm development protein (EED), and suppressor of zeste 12 (SUZ12). This review will summarize the latest insights into how PRC2 in mammalian cells regulates transcription to orchestrate the temporal and tissue-specific expression of genes to determine cell identity and cell-fate decisions. We will specifically describe how PRC2 dysregulation in different cell types can promote phenotypic plasticity and/or non-mutational epigenetic reprogramming, inducing the development of highly aggressive epithelial neuroendocrine carcinomas, including prostate, small cell lung, and Merkel cell cancer. With this, EZH2 has emerged as an important actionable therapeutic target in such cancers.
| S-EPMC9497807 | biostudies-literature
Project description:Polycomb Repressive Complex 2 (PRC2) catalyzes histone H3 lysine 27 tri-methylation (H3K27me3), an epigenetic modification associated with gene repression. H3K27me3 is enriched at the promoters of a large cohort of developmental genes in embryonic stem cells (ESCs). Loss of H3K27me3 leads to a failure of ESCs to properly differentiate, making it difficult to determine the precise roles of PRC2 during lineage commitment. Moreover, while studies suggest that PRC2 prevents DNA methylation, how these two epigenetic regulators coordinate to regulate lineage programs is poorly understood. Using several PRC2 mutant ESC lines that maintain varying levels of H3K27me3, we found that partial maintenance of H3K27me3 allowed for proper temporal activation of lineage genes during directed differentiation of ESCs to spinal motor neurons (SMNs). In contrast, genes that function to specify other lineages failed to be repressed in these cells, suggesting that PRC2 is also necessary for lineage fidelity. We also found that loss of H3K27me3 leads to a modest gain in DNA methylation at PRC2 target regions in both ESCs and in SMNs. Our study demonstrates a critical role for PRC2 in safeguarding lineage decisions and in protecting genes against inappropriate DNA methylation.
| S-EPMC4204901 | biostudies-literature
Project description:Despite the important role of Polycomb in genome-wide silencing, little is known of the specific biochemical mechanism by which it inactivates transcription. Here we address how recombinant Polycomb repressive complex 1 (PRC1) inhibits activated RNA polymerase II preinitiation complex (PIC) assembly using immobilized H3K27-methylated chromatin templates in vitro. Recombinant PRC1 inhibited transcription, but had little effect on binding of the activator as reported previously. In contrast, Mediator and the general transcription factors were blocked during assembly or dissociated from preassembled PICs. Importantly, among the PIC components, Tata Binding Protein (TBP) was the most resistant to eviction by PRC1. Immobilized template experiments using purified PRC1, transcription factor II D (TFIID), and Mediator indicate that PRC1 blocks the recruitment of Mediator, but not TFIID. We conclude that PRC1 functions to block or dissociate PICs by interfering with Mediator, but leaves TBP and perhaps TFIID intact, highlighting a specific mechanism for PRC1 transcriptional silencing. Analysis of published genome-wide datasets from mouse embryonic stem cells revealed that the Ring1b subunit of PRC1 and TBP co-enrich at developmental genes. Further, genes enriched for Ring1b and TBP are expressed at significantly lower levels than those enriched for Mediator, TBP, and Ring1b. Collectively, the data are consistent with a model in which PRC1 and TFIID could co-occupy genes poised for activation during development.
| S-EPMC3476247 | biostudies-literature
Project description:Correct timing of developmental phase transitions is critical for the survival and fitness of plants. Developmental phase transitions in plants are partially promoted by controlling relevant genes into active or repressive status. Polycomb Repressive Complex1 (PRC1) and PRC2, originally identified in Drosophila, are essential in initiating and/or maintaining genes in repressive status to mediate developmental phase transitions. Our review summarizes mechanisms in which the embryo-to-seedling transition, the juvenile-to-adult transition, and vegetative-to-reproductive transition in plants are mediated by PRC1 and PRC2, and suggests that PRC1 could act either before or after PRC2, or that they could function independently of each other. Details of the exact components of PRC1 and PRC2 in each developmental phase transitions and how they are recruited or removed will need to be addressed in the future.
| S-EPMC8305008 | biostudies-literature
Project description:During mouse embryogenesis, expression of the long non-coding RNA (lncRNA) Airn leads to gene repression and recruitment of Polycomb repressive complexes (PRCs) to varying extents over a 15-Mb domain. The mechanisms remain unclear. Using high-resolution approaches, we show in mouse trophoblast stem cells that Airn expression induces long-range changes to chromatin architecture that coincide with PRC-directed modifications and center around CpG island promoters that contact the Airn locus even in the absence of Airn expression. Intensity of contact between the Airn lncRNA and chromatin correlated with underlying intensity of PRC recruitment and PRC-directed modifications. Deletion of CpG islands that contact the Airn locus altered long-distance repression and PRC activity in a manner that correlated with changes in chromatin architecture. Our data imply that the extent to which Airn expression recruits PRCs to chromatin is controlled by DNA regulatory elements that modulate proximity of the Airn lncRNA product to its target DNA.
| S-EPMC10441531 | biostudies-literature