Paraspeckle Protein NONO Regulates Active Chromatin by Allosterically Stimulating NSD1
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ABSTRACT:
PROVIDER: PRJNA1301111 | ENA |
REPOSITORIES: ENA
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Project description:NSD1 is a key histone methyltransferase that catalyzes di-methylation of lysine 36 of histone H3 (H3K36me2), essential for active chromatin domains. While the loss of NSD1 activity halts embryonic development and its aberrant gain drives oncogenesis in leukemia and glioma, the regulatory mechanisms remain poorly understood. Here, we uncover that NSD1 requires allosteric activation through the aromatic pocket of its PWWP2 domain. Surprisingly, NSD1-PWWP2 binds to a non-canonical target, nuclear paraspeckle protein NONO, and this protein-protein interaction allosterically stimulates NSD1. Mouse embryonic stem cells (mESC) engineered with mutations in the aromatic pocket of NSD1-PWWP2 cannot differentiate into neural progenitor cells (NPC), and genetic depletion of NONO partially phenocopied this defect, potentially explaining the neurodevelopmental disorder phenotypes in NSD1- and NONO-deficient diseases. Our work uncovered a mechanism driving active chromatin domain formation, an implication in the interplay between nuclear paraspeckles and active chromatin, and a vulnerability of NSD1 for therapeutic interventions.
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Project description:Paraspeckle protein NONO attenuates vascular calcification by inhibiting BMP2 transcription
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Project description:Non-POU domain-containing octamer-binding protein (NONO) is a multifunctional member of the Drosophila behavior/human splicing (DBHS) protein family with DNA- and RNA-binding activity. Recent studies revealed that NONO is O-GlcNAcylated and dysregulated in various types of cancer. Excessive O-GlcNAcylation of target proteins has also been implicated in tumorigenesis. However, it is not known whether O-GlcNAcylation of NONO promotes cancer cell growth, and little is known about the effect of O-GlcNAcylation on the biological properties of NONO. This study identifies Thr440 as the primary NONO O-GlcNAcylation site and demonstrates its crucial role in the assembly of paraspeckles, an important subnuclear compartment that facilitates NONO-dependent transcriptional regulation in mammalian cells. We demonstrated that O-GlcNAcylation of NONO is required to maintain the expression of genes related to GO category “microtubule cytoskeleton organization involved in mitosis” and to suppress the expression of genes related to GO category “cellular response to type I interferon”. Moreover, stable depletion of NONO O-GlcNAcylation or NONO knockout significantly inhibited the growth of colon cancer cells. These findings highlight the importance of NONO and its O-GlcNAcylation status in modulating cell cycle progression, immune response, and tumorigenesis.
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Project description:We have previously shown that the Epstein-Barr virus (EBV) likely encodes hundreds of viral long non-coding RNAs (vlncRNAs) that are expressed during reactivation. Here we show that the EBV latency origin of replication (oriP) is transcribed bi-directionally during reactivation and that both leftward (oriPtLs) and rightward transcripts (oriPtRs) are largely localized in the nucleus. While the oriPtLs are most likely non-coding, at least some of the oriPtRs contain the BCRF1/vIL10 open reading frame. Nonetheless, oriPtR transcripts with long 5’UTRs may partially serve non-coding functions. Both oriPtL and oriPtR transcripts are expressed with late kinetics and their expression is inhibited by phosphonoacetic acid. RNA-seq analysis showed that oriPtLs and oriPtRs exhibited extensive “hyper-editing” at their Family of Repeat (FR) regions. RNA secondary structure prediction revealed that the FR region of both oriPtLs and oriPtRs may form large evolutionarily conserved and thermodynamically stable hairpins. The double-stranded RNA-binding protein and RNA-editing enzyme ADAR was found to bind to oriPtLs, likely facilitating editing of the FR hairpin. Further, the multifunctional paraspeckle protein, NONO, was found to bind to oriPt transcripts suggesting that oriPts interacts with the paraspeckle-based innate anti-viral immune pathway. Knock-down and ectopic expression of oriPtLs showed that it contributes to global viral lytic gene expression and viral DNA replication. Together, these results show that these new vlncRNAs interact with cellular innate immune pathways and that they help facilitate progression of the viral lytic cascade. RNA-seq analysis for oriPtL knockdown and overexpression experiments
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Project description:O-GlcNAcylation of NONO is Critical for Paraspeckle Component Assembly and Contributes to Tumorigenesis
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Project description:Nuclear receptor-binding SET domain protein 1 (NSD1) prototype is a family of mammalian histone methyltransferases (NSD1, NSD2/MMSET/WHSC1, NSD3/WHSC1L1) that are essential in development and are mutated in human acute myeloid leukemia (AML), overgrowth syndromes, multiple myeloma and lung cancers. In AML, the recurring t(5;11)(q35;p15.5) translocation fuses NSD1 to nucleoporin-98 (NUP98). Here, we present the first characterization of the transforming properties and molecular mechanisms of NUP98-NSD1. We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes. Mechanistically, NUP98-NSD1 binds genomic elements adjacent to HoxA7 and HoxA9, maintains histone H3 Lys 36 (H3K36) methylation and histone acetylation, and prevents EZH2-mediated transcriptional repression of the Hox-A locus during differentiation. Deletion of the NUP98 FG-repeat domain, or mutations in NSD1 that inactivate the H3K36 methyltransferase activity or that prevent binding of NUP98-NSD1 to the Hox-A locus precluded both Hox-A gene activation and myeloid progenitor immortalization. We propose that NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements. This report is the first to link deregulated H3K36 methylation to tumorigenesis and to link NSD1 to transcriptional regulation of the Hox-A locus. Experiment Overall Design: Total RNA was extracted from stably transformed progenitors cultured in vitro and the expression levels of mRNA transcripts quantified using the Affymetrix GeneChip Mouse Genome 430 2.0 array, as previously described. The GEO database accession numbers: for progenitors immortalized by HoxA9 (GSM190542, GSM190546, GSM190547); for progenitors immortalized by coexpressed HoxA9 plus Meis1 (GSM190548, GSM190549, GSM190550); for progenitors immortalized by NUP98-NSD1 (GSM190551, GSM190552, GSM190553); and for progenitors immortalized by MLL-ENL (GSM190554). Experiment Overall Design: NOTE: CEL files and dChip data were requested by GEO but not provided.
2008-06-11 | E-GEOD-10071 | biostudies-arrayexpress
Project description:Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1+/- specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1+/- specific signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing. Bisulphite converted DNA from 122 samples were hybridized to the Illumina Infinium 450k Human Methylation Beadchip array.
2015-12-16 | E-GEOD-74432 | 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-2895 | biostudies-arrayexpress