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Nono, a novel bivalent domain factor, regulates Erk signaling and mouse embryonic stem cell pluripotency [ChIP-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE73426 | GEO | 2016/10/18

SECONDARY ACCESSION(S): PRJNA296947

REPOSITORIES: GEO

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Nono, a novel bivalent domain factor, regulates Erk signaling and mouse embryonic stem cell pluripotency [RNA-Seq]

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

NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

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

NONO mutations cause syndromic intellectual disability and inhibitory synaptic defects

2015-09-02 | E-MTAB-2894 | biostudies-arrayexpress

NONO knockdown RNA-seq and neuroblastoma PARCLIP analysis of NONO

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

Integrated analysis identifies key determinants of embryonic stem cell identity and homeostasis

Project description:Despite RNAi-based screens to uncover genes controlling embryonic stem cell (ESC) identity, the pluripotency network remains poorly characterized, as does the precise molecular mechanisms underlying the balance between self-renewal and differentiation. Here we carried out a systematic meta-analysis of published gene expression data to rank-order genes based on their likelihood of regulating ESC identity. Not only did our analysis correctly rank known pluripotency-associated genes atop the list, but it also helped unearth many novel determinants of ESC identity including several components of functionally distinct complexes, as determined using RNAi. We focus on our top-hit Nucleolin, and characterize its mechanistic role in the maintenance of ESC homeostasis by shielding from differentiation-inducing redox imbalance-induced oxidative stress. Notably, we identify a conceptually novel mechanism involving a Nucleolin-dependent bistable switch regulating the homeostatic balance between self-renewal and differentiation in ESCs. Our gene ranks represent a rich and valuable resource for uncovering novel ESC regulators. Microarray gene expression profiling in E14Tg2a mESCs after transfection with indicated siRNAs: Ncl siRNA #1 (Invitrogen, 17975-MSS206961) Ncl siRNA #2 (Invitrogen, 17975-MSS275939), and Control siRNA duplex targeting firefly luciferase.

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Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity [expression profiling]

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2012-01-06 | E-GEOD-34886 | biostudies-arrayexpress

Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity [MRE-seq]

Project description:The TET family of FE(II) and 2-oxoglutarate-dependent enzymes (Tet1/2/3) promote DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), which they further oxidize into 5-formylcytosine and 5-carboxylcytosine. Tet1 is robustly expressed in mouse embryonic stem cells (mESCs) and has been implicated in mESC maintenance. Here we demonstrate that, unlike genetic deletion, RNAi-mediated depletion of Tet1 in mESCs led to a significant reduction in 5hmC and loss of mESC identity. The differentiation phenotype due to Tet1 depletion positively correlated with the extent of 5hmC loss. Meta-analyses of genomic datasets suggested interaction between Tet1 and leukemia inhibitory factor (LIF) signaling. LIF signaling is known to promote self-renewal and pluripo-tency in mESCs partly by opposing MAPK/ERK mediated differentiation. Withdrawal of LIF leads to differentiation of mESCs. We discovered that Tet1 depletion impaired LIF-dependent Stat3-mediated gene activation by affecting Stat3's ability to bind to its target sites on chromatin. Nanog overexpression or inhibition of MAPK/ERK signaling, both known to maintain mESCs in the absence of LIF, rescued Tet1 depletion, further supporting the dependence of LIF/Stat3 signaling on Tet1. These data support the conclusion that analysis of mESCs in the hours/days immediately following efficient Tet1 depletion reveals Tet1’s normal physiological role in maintaining the pluripotent state that may be subject to homeostatic compensation in genetic models. Genome-wide mapping of 5hmC and microarray gene expression profiling in E14Tg2a mESCs after transfection with indicated siRNAs: Tet1 siRNA #1 (Invitrogen, MSS284895), Tet1 siRNA #2 (Invitrogen, MSS284897), and Control siRNA duplex targeting firefly luciferase.

2012-01-06 | E-GEOD-34887 | biostudies-arrayexpress

Paraspeckle protein NONO attenuates vascular calcification by inhibiting BMP2 transcription

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2024-01-10 | GSE252244 | GEO

NONO detects the nuclear HIV capsid to promote cGAS-mediated innate immune activation

Project description:Detection of viruses by innate immune sensors induces protective antiviral immunity. The viral DNA sensor cGAS is necessary for detection of HIV by human dendritic cells and macrophages. However, synthesis of HIV DNA during infection is not sufficient for immune activation. The capsid protein, which associates with viral DNA, has a pivotal role in enabling cGAS-mediated immune activation. We now find that NONO is an essential sensor of the HIV capsid in the nucleus. NONO protein directly binds capsid with higher affinity for weakly pathogenic HIV-2 than highly pathogenic HIV-1. Upon infection, NONO is essential for cGAS activation by HIV and cGAS association with HIV DNA in the nucleus. NONO recognizes a conserved region in HIV capsid with limited tolerance for escape mutations. Detection of nuclear viral capsid by NONO to promote DNA sensing by cGAS reveals an innate strategy to achieve distinction of viruses from self in the nucleus.

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Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions

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