Nono, a novel bivalent domain factor, regulates Erk signaling and mouse embryonic stem cell pluripotency
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ABSTRACT:
PROVIDER: PRJNA342617 | ENA |
REPOSITORIES: ENA
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Project description:Here we report that Nono instead functions as a chromatin regulator cooperating with Erk to regulate mESC pluripotency. We demonstrate that Nono loss leads to robust self-renewing mESCs with enhanced expression of Nanog and Klf4, epigenome and transcriptome re-patterning to a “ground-like state” with global reduction of H3K27me3 and DNA methylation resembling the Erk inhibitor PD03 treated mESCs and 2i (both GSK and Erk kinase inhibitors)-induced “ground state”. Mechanistically, Nono and Erk co-bind at a subset of development-related, bivalent genes. Ablation of Nono compromises Erk activation and RNA polymerase II C-terminal Domain serine 5 phosphorylation, and while inactivation of Erk evicts Nono from chromatin, revealing reciprocal regulation. Furthermore, Nono loss results in a compromised activation of its target bivalent genes upon differentiation and the differentiation itself. These findings reveal an unanticipated role of Nono in collaborating with Erk signaling to regulate the integrity of bivalent domain and mESC pluripotency.
2016-10-18 | GSE86817 | GEO
Project description:Here we report that NONO, a nuclear para-speckle component, instead functions as a chromatin regulator in mESCs acting in the ERK signaling pathway to regulate the balance between ground state versus mESCs primed for differentiation. NONO loss increases a \u201cground-like\u201d population of mESCs favoring self-renewal and more resist to differentiation, partially mimicking the effects of 2i. Mechanistically, NONO and ERK mainly co-binds a subset of development related, bivalent genes. Importantly, NONO and ERK reciprocally regulate one another, i.e. NONO regulates ERK activation while ERK controls NONO chromatin association, forming a self-reinforcing feedback loop. Our findings thus reveal a cell intrinsic mechanism involving NONO and ERK, which impact the balance between self-renewal and differentiation, respectively.
2016-10-18 | GSE73426 | GEO
Project description: Not available
| S-EPMC5086807 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-10-18 | GSE86818 | GEO
Project description:Nono, a novel bivalent domain factor, regulates Erk signaling and mouse embryonic stem cell pluripotency [RNA-Seq]
| PRJNA342629 | ENA
Project description:The bivalent domain at promoter region is a unique epigenetic feature poised for activation or repression during cell differentiation in embryonic stem cell. However, the function of bivalent domains in already differentiated cells remains exclusive. By profiling the epigenetic landscape of endothelial cells during VEGFA stimulation, we discovered that bivalent domains are widespread in endothelial cells and preferentially marked genes responsive to VEGFA. The bivalent domains responsive to VEGFA have more permissive chromatin environment comparing to other bivalent domains. The initial activation of bivalent genes depends on RNAPII pausing release induced by EZH1 rather than removal of H3K27me3. The later suppression of bivalent gene expression depended on KDM5A recruitment by its interaction with PRC2. Importantly, EZH1 promoted both in vitro and in vivo angiogenesis by upregulating EGR3, whereas KDM5A dampened angiogenesis. Collectively, this study demonstrated a novel dual function of bivalent domains in endothelial cells to control VEGF responsiveness and angiogenesis.
2020-10-17 | GSE139077 | GEO
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2895 | biostudies-arrayexpress
Project description:Identifying causes of sporadic intellectual disability remains a considerable medical challenge. Here, we demonstrate that null mutations in the NONO gene, a member of the Drosophila Behavior Human Splicing (DBHS) protein family, are a novel cause of X-linked syndromic intellectual disability. Comparing humans to Nono-deficient mice revealed related behavioral and craniofacial anomalies, as well as global transcriptional dysregulation. Nono-deficient mice also showed deregulation of a large number of synaptic transcripts, causing a disorganization of inhibitory synapses, with impaired postsynaptic scaffolding of gephyrin. Alteration of gephyrin clustering could be rescued by over-expression of Gabra2 in NONO-compromised neurons. These findings link NONO to intellectual disability and first highlight the key role of DBHS proteins in functional organization of GABAergic synapses.
2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress
Project description:RNA-binding proteins emerge as effectors of the DNA damage response (DDR). The multifunctional non-POU domain-containing octamer-binding protein NONO/p54nrb marks nuclear paraspeckles in unperturbed cells, but also undergoes re-localization to the nucleolus upon induction of DNA double-strand breaks (DSBs). However, NONO nucleolar re-localization is poorly understood. Here we show that the topoisomerase II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-inducible antisense intergenic non-coding RNA (asincRNA) in human cancer cells. Such transcripts originate from distinct nucleolar intergenic spacer regions and form DNA–RNA hybrids to tether NONO to the nucleolus in an RNA recognition motif 1 domain-dependent manner. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of a subset of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signalling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.
2024-01-16 | GSE233594 | GEO
Project description:siRNA knockdown of NONO mRNA followed by RNA-seq was carried out in the KELLY neuroblasotma cell line. In order to determine potential regulatory targets of NONO protein, we performed differential expression analysis. To identify the RNA targets of NONO in neuroblastoma, we carried out PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) using an antibody recognising NONO protein.
2023-01-28 | GSE114376 | GEO