The NORAD lncRNA assembles a topoisomerase complex critical for DNA replication and genome stability
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Steven A. Carr
PROVIDER: MSV000082561 | MassIVE | Sat Jun 30 08:32:00 BST 2018
REPOSITORIES: MassIVE
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Project description:Rusu V, Hoch E, Mercader JM, Tenen DE, Gymrek M, Hartigan CR, von Grotthuss M, Fontanillas P, Spooner A, Guzman G, Carr SA, Schenone M, Ng MCY, Chen BH, MEDIA Consortium, SIGMA T2D Consortium, Orozco L, Altshuler DM, Schreiber SL, Florez JC, Jacobs SBR, Lander ES. 2017 Cell. Type 2 Diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype in SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a reduced set of tightly-linked common variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreased expression of the SLC16A11 gene in human liver and (2) missense changes in the SLC16A11 protein that disrupt a key interaction with the chaperone basigin, thereby reducing plasma membrane localization. Both independent mechanisms reduce SLC16A11 function, and together suggest that SLC16A11 is the causal gene. To gain insight into how disruption of SLC16A11 impacts T2D risk, we investigate this previously uncharacterized transporter and categorize SLC16A11 as a proton-coupled monocarboxylate transporter. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D.
2017-05-23 | MSV000081105 | MassIVE
Project description:Basak A, Munschauer M, Lareau CA, Montbleau KE, Ulirsch JC, Hartigan CR, Schenone M, Lian J, Wang Y, Huang Y, Wu X, Gehrke L, Rice CM, An X, Christou HA, Mohandas N, Carr SA, Orkin SH, Chen JJ, Lander ES, and Sankaran VG.
Increased production of the beta-like gamma-globin genes that form fetal hemoglobin can ameliorate the severity of sickle cell disease and beta-thalassemia, the major hemoglobin disorders. BCL11A is a key repressor of the gamma-globin genes and is expressed in a developmental stage-specific manner to regulate the physiologic fetal-to-adult hemoglobin switch. Despite extensive studies, the upstream mechanisms underlying the developmental expression of BCL11A and hemoglobin switching in humans have remained mysterious. Here we show that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. While BCL11A mRNA is comparably expressed at all developmental stages in erythroid cells, robust protein expression only occurs in adult erythroid cells. Importantly, at the earlier stages of development, the observed reduction in protein expression is attributable to decreased synthesis and not increased degradation of BCL11A. While BCL11A protein is not well synthesized at these earlier stages of development, its mRNA curiously continues to be associated with ribosomes. Through unbiased proteomic analyses in erythroid cells, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a reciprocal pattern to BCL11A, directly interacts with ribosomes. We show that the observed suppression of BCL11A protein translation is mediated by LIN28B through a direct interaction with BCL11A mRNA and independent of its role in let-7 microRNA biogenesis. Finally, we show that BCL11A is the major functional target in LIN28B-mediated fetal hemoglobin induction. Our results reveal a previously unappreciated regulatory mechanism underlying human hemoglobin switching and illuminate opportunities for developing improved treatments for sickle cell disease and beta-thalassemia.
2019-10-09 | MSV000084443 | MassIVE
Project description:Cistus ladanifer L. is a common shrub endemic to the Mediterranean that is highly concentrated in condensed tannins (CT). CT form complexes with dietary protein that resist microbial degradation in the rumen, which enhances dietary protein utilization in ruminant diets. The objective of this study was to evaluate the utilization of CT in the diet of lambs on the proteomes of muscle, hepatic and adipose tissues. Twenty-four white merino ram lambs were divided in three groups (n=8) fed on different diets: control (16% crude protein - CP), reduced protein (12% CP) and reduced protein treated with CT extract. At the end of the trial, lambs were slaughtered and the longissimus lumborum muscle, hepatic and peri-renal adipose tissues sampled. A two-way approach was used for shotgun proteomic analysis: 2D-DIGE (gel-based) and nanoLC-MS (gel-free). In the muscle, control lambs had lower abundance proteins that partake in the glycolysis pathway. With dietary 12 % CP, lambs had higher abundance of Fe-carrying proteins in the hepatic tissue. Lambs with dietary CT had higher abundance of hepatic flavin reductase. In the adipose tissue, control lambs had lower abundance of fatty-acid synthase. In conclusion, CT inclusion influences specific pathways in lamb tissues.
2021-02-16 | PXD015689 | Pride
Project description:Khajuria RK, Munschauer M, Ulirsch JC, Fiorini C, Leif S. Ludwig LS, McFarland SK, Abdulhay NJ, Specht H, Keshishian H, Mani DR, Jovanovic M, Ellis SR, Fulco CP, Engreitz JM, Schütz S, Lian J, Gripp KW,Weinberg OK, Pinkus GS, Gehrke L, Regev A, Lander ES, Gazda HT, Lee WY, Panse VG, Carr SA, Sankaran VG. Cell 2018, 173, 90–103. https://doi.org/10.1016/j.cell.2018.02.036.
Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.
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Project description:Total RNA samples from human bronchial epithelial BEAS-2B passage-matched control cells and Cr(VI)-transofmred BEAS-2B cells were submitted to ArraySatr for total RNA m6A epitranscriptomic microarray analysis
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