Browsing by keyword "Heterogeneous-Nuclear Ribonucleoproteins"

Now showing items 1-3 of 3

    • A long noncoding RNA mediates both activation and repression of immune response genes
      Carpenter, Susan; Aiello, Daniel; Atianand, Maninjay K.; Ricci, Emiliano P.; Gandhi, Pallavi; Hall, Lisa L.; Byron, Meg; Monks, Brian G.; Henry-Bezy, Meabh; Lawrence, Jeanne B.; et al. (2013-08-16)
      An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response.

    • An SRp75/hnRNPG Complex Interacting with hnRNPE2 Regulates the 5' Splice Site of Tau Exon 10, Whose Misregulation Causes Frontotemporal Dementia
      Wang, Yan; Wang, Junning; Gao, Lei; Stamm, Stefan; Andreadis, Athena (2011-10-11)
      Tau is a neuronal-specific microtubule-associated protein that plays an important role in establishing neuronal polarity and maintaining the axonal cytoskeleton. Aggregated tau is the major component of neurofibrillary tangles (NFTs), structures present in the brains of people affected by neurodegenerative diseases called tauopathies. Tauopathies include Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism (FTDP-17), the early onset dementia observed in Down syndrome (DS; trisomy 21) and the dementia component of myotonic dystrophy type 1 (DM1). Splicing misregulation of adult-specific exon 10, which codes for a microtubule binding domain, results in expression of abnormal ratios of tau isoforms, leading to FTDP-17. Positions 3 to 19 of the intron downstream of exon 10 define a hotspot of splicing regulation: the region diverges between humans and rodents, and point mutations within it result in tauopathies. In this study, we investigated three regulators of exon 10 splicing: serine/arginine-rich protein SRp75 and heterogeneous nuclear ribonucleoproteins hnRNPG and hnRNPE2. SRp75 and hnRNPG inhibit splicing of exon 10 whereas hnRNPE2 activates it. Using co-transfections, co-immunoprecipitations and RNAi we discovered that SRp75 binds to the proximal downstream intron of tau exon 10 at the FTDP-17 hotspot region; and that hnRNPG and hnRNPE2 interact with SRp75. Thus, increased exon 10 inclusion in FTDP mutants may arise from weakened SRp75 binding. This work provides insights into the splicing regulation of the tau gene and into possible strategies for correcting the imbalance in tauopathies caused by changes in the ratio of exon 10.

    • Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations
      Wang, Yan; Gao, Lei; Tse, Sze-Wah; Andreadis, Athena (2009-11-17)
      The microtubule-associated protein tau is important to normal neuronal activity in the mammalian nervous system. Aggregated tau is the major component of neurofibrillary tangles (NFTs), structures present in the brains of people affected by neurodegenerative diseases called tauopathies. Tauopathies include Alzheimer's disease (AD), frontotemporal dementia with Parkinsonism (FTDP) and the early-onset dementia observed in Down syndrome (DS; trisomy 21). Splicing misregulation of adult-specific exon 10 results in expression of abnormal ratios of tau isoforms, leading to FTDP. Positions +3 to +19 of the intron downstream of exon 10 define a hotspot: Point mutations in it result in tauopathies. All these mutations increase exon 10 inclusion except for mutation +19, which almost entirely excludes exon 10. To investigate the tau connection between DS and AD, we examined splicing factors located on chromosome 21 for their effect on tau exon 10. By co-transfections, co-immunoprecipitations and RNAi constructs, we discovered that one of them, hnRNPE3 (PCBP3), modestly activates splicing of exon 10 by interacting with its proximal downstream intron around position +19. These results, coupled with the developmental profile of hnRNPE3, suggest a pathogenic role for splicing factors on chromosome 21 in neurodegenerative diseases with tangles and create a connection between tau splicing and the early-onset dementia of Down syndrome.