TY - CHAP AU - Wenzl, Bernhard ED - Parker, Joshua ED - Poole, Ralph ID - 1075 SN - 978-3643908124 T2 - Austria and America: 20th-Century Cross-Cultural Encounters TI - An American in Allied-occupied Austria: John Dos Passos Reports on "The Vienna Frontier" VL - 15 ER - TY - JOUR AB - Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML. AU - Franks, Tobias M. AU - McCloskey, Asako AU - Shokhirev, Maxim Nikolaievich AU - Benner, Chris AU - Rathore, Annie AU - HETZER, Martin W ID - 11066 IS - 22 JF - Genes & Development KW - Developmental Biology KW - Genetics SN - 0890-9369 TI - Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells VL - 31 ER - TY - JOUR AB - Neural progenitor cells (NeuPCs) possess a unique nuclear architecture that changes during differentiation. Nucleoporins are linked with cell-type-specific gene regulation, coupling physical changes in nuclear structure to transcriptional output; but, whether and how they coordinate with key fate-determining transcription factors is unclear. Here we show that the nucleoporin Nup153 interacts with Sox2 in adult NeuPCs, where it is indispensable for their maintenance and controls neuronal differentiation. Genome-wide analyses show that Nup153 and Sox2 bind and co-regulate hundreds of genes. Binding of Nup153 to gene promoters or transcriptional end sites correlates with increased or decreased gene expression, respectively, and inhibiting Nup153 expression alters open chromatin configurations at its target genes, disrupts genomic localization of Sox2, and promotes differentiation in vitro and a gliogenic fate switch in vivo. Together, these findings reveal that nuclear structural proteins may exert bimodal transcriptional effects to control cell fate. AU - Toda, Tomohisa AU - Hsu, Jonathan Y. AU - Linker, Sara B. AU - Hu, Lauren AU - Schafer, Simon T. AU - Mertens, Jerome AU - Jacinto, Filipe V. AU - HETZER, Martin W AU - Gage, Fred H. ID - 11067 IS - 5 JF - Cell Stem Cell KW - Cell Biology KW - Genetics KW - Molecular Medicine SN - 1934-5909 TI - Nup153 interacts with Sox2 to enable bimodal gene regulation and maintenance of neural progenitor cells VL - 21 ER - TY - JOUR AB - Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging. AU - Buchwalter, Abigail AU - HETZER, Martin W ID - 11065 JF - Nature Communications KW - General Physics and Astronomy KW - General Biochemistry KW - Genetics and Molecular Biology KW - General Chemistry SN - 2041-1723 TI - Nucleolar expansion and elevated protein translation in premature aging VL - 8 ER - TY - JOUR AB - We present spectroscopic follow-up observations of CR7 with ALMA, targeted at constraining the infrared (IR) continuum and [C II]158 mm line-emission at high spatial resolution matched to the HST/WFC3 imaging. CR7 is a luminous Lyα emitting galaxy at z = 6.6 that consists of three separated UV-continuum components. Our observations reveal several well-separated components of [C II] emission. The two most luminous components in [C II] coincide with the brightest UV components (A and B), blueshifted by »150 km s−1 with respect to the peak of Lyα emission. Other [C II] components are observed close to UV clumps B and C and are blueshifted by »300 and ≈80 km s−1 with respect to the systemic redshift. We do not detect FIR continuum emission due to dust with a 3σ limiting luminosity LIR T L d 35 K 3.1 10 = <´ 10 ( ) . This allows us to mitigate uncertainties in the dust-corrected SFR and derive SFRs for the three UV clumps A, B, and C of 28, 5, and 7 M yr−1. All clumps have [C II] luminosities consistent within the scatter observed in the local relation between SFR and L[ ] C II , implying that strong Lyα emission does not necessarily anti-correlate with [C II] luminosity. Combining our measurements with the literature, we show that galaxies with blue UV slopes have weaker [C II] emission at fixed SFR, potentially due to their lower metallicities and/or higher photoionization. Comparison with hydrodynamical simulations suggests that CR7ʼs clumps have metallicities of 0.1 Z Z 0.2 < < . The observed ISM structure of CR7 indicates that we are likely witnessing the build up of a central galaxy in the early universe through complex accretion of satellites. AU - Matthee, Jorryt J AU - Sobral, D. AU - Boone, F. AU - Röttgering, H. AU - Schaerer, D. AU - Girard, M. AU - Pallottini, A. AU - Vallini, L. AU - Ferrara, A. AU - Darvish, B. AU - Mobasher, B. ID - 11518 IS - 2 JF - The Astrophysical Journal KW - Space and Planetary Science KW - Astronomy and Astrophysics KW - dark ages KW - reionization KW - first stars – galaxies: formation – galaxies: high-redshift – galaxies: ISM – galaxies: kinematics and dynamics SN - 0004-637X TI - ALMA reveals metals yet no dust within multiple components in CR7 VL - 851 ER -