59 research outputs found

    P-TEFb Regulates Transcriptional Activation in Non-coding RNA Genes

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    Many non-coding RNAs (ncRNAs) serve as regulatory molecules in various physiological pathways, including gene expression in mammalian cells. Distinct from protein-coding RNA expression, ncRNA expression is regulated solely by transcription and RNA processing/stability. It is thus important to understand transcriptional regulation in ncRNA genes but is yet to be known completely. Previously, we identified that a subset of mammalian ncRNA genes is transcriptionally regulated by RNA polymerase II (Pol II) promoter-proximal pausing and in a tissue-specific manner. In this study, human ncRNA genes that are expressed in the early G1 phase, termed immediate early ncRNA genes, were monitored to assess the function of positive transcription elongation factor b (P-TEFb), a master Pol II pausing regulator for protein-coding genes, in ncRNA transcription. Our findings indicate that the expression of many ncRNA genes is induced in the G0–G1 transition and regulated by P-TEFb. Interestingly, a biphasic characteristic of P-TEFb-dependent transcription of serum responsive ncRNA genes was observed: Pol II carboxyl-terminal domain phosphorylated at serine 2 (S2) was largely increased in the transcription start site (TSS, -300 to +300) whereas overall, it was decreased in the gene body (GB, > +350) upon chemical inhibition of P-TEFb. In addition, the three representative, immediate early ncRNAs, whose expression is dependent on P-TEFb, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), nuclear enriched abundant transcript 1 (NEAT1), and X-inactive specific transcript (XIST), were further analyzed for determining P-TEFb association. Taken together, our data suggest that transcriptional activation of many human ncRNAs utilizes the pausing and releasing of Pol II, and that the regulatory mechanism of transcriptional elongation in these genes requires the function of P-TEFb. Furthermore, we propose that ncRNA and mRNA transcription are regulated by similar mechanisms while P-TEFb inhibition unexpectedly increases S2 Pol II phosphorylation in the TSSs in many ncRNA genes.One Sentence Summary: P-TEFb regulates Pol II phosphorylation for transcriptional activation in many stimulus-inducible ncRNA genes

    Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

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    © 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice11Nsciescopu

    The JCMT BISTRO Survey: A Spiral Magnetic Field in a Hub-filament Structure, Monoceros R2

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    We present and analyze observations of polarized dust emission at 850 ÎŒm toward the central 1 7 1 pc hub-filament structure of Monoceros R2 (Mon R2). The data are obtained with SCUBA-2/POL-2 on the James Clerk Maxwell Telescope (JCMT) as part of the B-fields in Star-forming Region Observations survey. The orientations of the magnetic field follow the spiral structure of Mon R2, which are well described by an axisymmetric magnetic field model. We estimate the turbulent component of the magnetic field using the angle difference between our observations and the best-fit model of the underlying large-scale mean magnetic field. This estimate is used to calculate the magnetic field strength using the Davis–Chandrasekhar–Fermi method, for which we also obtain the distribution of volume density and velocity dispersion using a column density map derived from Herschel data and the C18O (J = 3 - 2) data taken with HARP on the JCMT, respectively. We make maps of magnetic field strengths and mass-to-flux ratios, finding that magnetic field strengths vary from 0.02 to 3.64 mG with a mean value of 1.0 \ub1 0.06 mG, and the mean critical mass-to-flux ratio is 0.47 \ub1 0.02. Additionally, the mean Alfv\ue9n Mach number is 0.35 \ub1 0.01. This suggests that, in Mon R2, the magnetic fields provide resistance against large-scale gravitational collapse, and the magnetic pressure exceeds the turbulent pressure. We also investigate the properties of each filament in Mon R2. Most of the filaments are aligned along the magnetic field direction and are magnetically subcritical

    The JCMT BISTRO Survey: Studying the Complex Magnetic Field of L43

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    We present observations of polarized dust emission at 850 ÎŒm from the L43 molecular cloud, which sits in the Ophiuchus cloud complex. The data were taken using SCUBA-2/POL-2 on the James Clerk Maxwell Telescope as a part of the BISTRO large program. L43 is a dense (NH 10 22 2 ~ –1023 cm−2) complex molecular cloud with a submillimeter-bright starless core and two protostellar sources. There appears to be an evolutionary gradient along the isolated filament that L43 is embedded within, with the most evolved source closest to the Sco OB2 association. One of the protostars drives a CO outflow that has created a cavity to the southeast. We see a magnetic field that appears to be aligned with the cavity walls of the outflow, suggesting interaction with the outflow. We also find a magnetic field strength of up to ∌160 ± 30 ÎŒG in the main starless core and up to ∌90 ± 40 ÎŒG in the more diffuse, extended region. These field strengths give magnetically super- and subcritical values, respectively, and both are found to be roughly trans-AlfvĂ©nic. We also present a new method of data reduction for these denser but fainter objects like starless cores

    Magnetic Fields toward Ophiuchus-B Derived from SCUBA-2 Polarization Measurements

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    We present the results of dust emission polarization measurements of Ophiuchus-B (Oph-B) carried out using the Submillimetre Common-User Bolometer Array 2 (SCUBA-2) camera with its associated polarimeter (POL-2) on the James Clerk Maxwell Telescope in Hawaii. This work is part of the B-fields in Star-forming Region Observations survey initiated to understand the role of magnetic fields in star formation for nearby star-forming molecular clouds. We present a first look at the geometry and strength of magnetic fields in Oph-B. The field geometry is traced over ~0.2 pc, with clear detection of both of the sub-clumps of Oph-B. The field pattern appears significantly disordered in sub-clump Oph-B1. The field geometry in Oph-B2 is more ordered, with a tendency to be along the major axis of the clump, parallel to the filamentary structure within which it lies. The degree of polarization decreases systematically toward the dense core material in the two sub-clumps. The field lines in the lower density material along the periphery are smoothly joined to the large-scale magnetic fields probed by NIR polarization observations. We estimated a magnetic field strength of 630 ± 410 ÎŒG in the Oph-B2 sub-clump using a Davis–Chandrasekhar–Fermi analysis. With this magnetic field strength, we find a mass-to-flux ratio λ = 1.6 ± 1.1, which suggests that the Oph-B2 clump is slightly magnetically supercritical

    Filamentary Network and Magnetic Field Structures Revealed with BISTRO in the High-mass Star-forming Region NGC 2264: Global Properties and Local Magnetogravitational Configurations

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    We report 850 Όm continuum polarization observations toward the filamentary high-mass star-forming region NGC 2264, taken as part of the B-fields In STar forming Regions Observations large program on the James Clerk Maxwell Telescope. These data reveal a well-structured nonuniform magnetic field in the NGC 2264C and 2264D regions with a prevailing orientation around 30° from north to east. Field strength estimates and a virial analysis of the major clumps indicate that NGC 2264C is globally dominated by gravity, while in 2264D, magnetic, gravitational, and kinetic energies are roughly balanced. We present an analysis scheme that utilizes the locally resolved magnetic field structures, together with the locally measured gravitational vector field and the extracted filamentary network. From this, we infer statistical trends showing that this network consists of two main groups of filaments oriented approximately perpendicular to one another. Additionally, gravity shows one dominating converging direction that is roughly perpendicular to one of the filament orientations, which is suggestive of mass accretion along this direction. Beyond these statistical trends, we identify two types of filaments. The type I filament is perpendicular to the magnetic field with local gravity transitioning from parallel to perpendicular to the magnetic field from the outside to the filament ridge. The type II filament is parallel to the magnetic field and local gravity. We interpret these two types of filaments as originating from the competition between radial collapsing, driven by filament self-gravity, and longitudinal collapsing, driven by the region's global gravity

    JCMT BISTRO Survey: Magnetic Fields within the Hub-filament Structure in IC 5146

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    We present the 850 ÎŒm polarization observations toward the IC 5146 filamentary cloud taken using the Submillimetre Common-User Bolometer Array 2 (SCUBA-2) and its associated polarimeter (POL-2), mounted on the James Clerk Maxwell Telescope, as part of the B-fields In STar forming Regions Observations. This work is aimed at revealing the magnetic field morphology within a core-scale (lesssim1.0 pc) hub-filament structure (HFS) located at the end of a parsec-scale filament. To investigate whether the observed polarization traces the magnetic field in the HFS, we analyze the dependence between the observed polarization fraction and total intensity using a Bayesian approach with the polarization fraction described by the Rice likelihood function, which can correctly describe the probability density function of the observed polarization fraction for low signal-to-noise ratio data. We find a power-law dependence between the polarization fraction and total intensity with an index of 0.56 in A V ~ 20–300 mag regions, suggesting that the dust grains in these dense regions can still be aligned with magnetic fields in the IC 5146 regions. Our polarization maps reveal a curved magnetic field, possibly dragged by the contraction along the parsec-scale filament. We further obtain a magnetic field strength of 0.5 ± 0.2 mG toward the central hub using the Davis–Chandrasekhar–Fermi method, corresponding to a mass-to-flux criticality of ~1.3 ± 0.4 and an AlfvĂ©nic Mach number of <0.6. These results suggest that gravity and magnetic field are currently of comparable importance in the HFS and that turbulence is less important
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