| 1. |
- Behm, Mikaela, 1986-, et al.
(författare)
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Synaptic expression and regulation of miRNA editing in the brain
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the brain, sophisticated networks of RNA regulatory events tightly control gene expression in order to achieve proper brain function. We and others have previously shown that several miRNAs, encoded within the miR-379-410 cluster, are subjected to A-to-I RNA editing. In the present study we conclude these edited miRNAs to be transcribed as a single long consecutive transcript, however the maturation into functional forms of miRNAs is regulated individually. In seven of the miRNAs, subjected to editing, we analyze how editing relates to miRNA maturation. Of particular interest has been maturation of miR-381-3p and miR-376b-3p, both important for neuronal plasticity, dendrite outgrowth and neuronal homeostasis. Most of the edited miRNAs from the cluster, are highly edited in their unprocessed primary transcript, including miR-381-3p and miR-376b-3p. However, editing in miR-381-3p is almost entirely absent in the mature form, while editing is increased in the mature form of miR-376b-3p compared to the primary transcript. We propose that ADAR1 positively influences the maturation of pri-miR-381 in an editing independent manner. In pri-miR-376b we hypothesize that ADAR1 and ADAR2 competes for editing, and while ADAR2 inhibits miRNA maturation, ADAR1 editing is frequently present in the mature miR-376b-3p. We further show that miR-381-3p and miR-376b-3p regulate the dendritically expressed Pumilio 2 (Pum2) protein. By next generation RNA sequencing (NGS RNA-seq) on purified synaptoneurosomes, we show that miR-381-3p is highly expressed at the synapse, suggesting its functional role in locally regulating Pum2. Furthermore, we identify a set of highly expressed miRNAs at the synapse, which may act locally to target synaptic mRNAs.
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| 2. |
- Chammiran, Daniel, et al.
(författare)
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A distant cis acting intronic element induces site-selective RNA editing
- 2012
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 40:19, s. 9876-9886
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Tidskriftsartikel (refereegranskat)abstract
- Transcripts have been found to be site selectively edited from adenosine-to-inosine (A-to-I) in the mammalian brain, mostly in genes involved in neurotransmission. While A-to-I editing occurs at double-stranded structures, other structural requirements are largely unknown. We have investigated the requirements for editing at the I/M site in the Gabra-3 transcript of the GABA(A) receptor. We identify an evolutionarily conserved intronic duplex, 150 nt downstream of the exonic hairpin where the I/M site resides, which is required for its editing. This is the first time a distant RNA structure has been shown to be important for A-to-I editing. We demonstrate that the element also can induce editing in related but normally not edited RNA sequences. In human, thousands of genes are edited in duplexes formed by inverted repeats in non-coding regions. It is likely that numerous such duplexes can induce editing of coding regions throughout the transcriptome.
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| 3. |
- Ekdahl, Ylva, et al.
(författare)
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A-to-I editing of microRNAs in the mammalian brain increases during development
- 2012
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 22:8, s. 1477-1487
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Tidskriftsartikel (refereegranskat)abstract
- Adenosine-to-inosine (A-to-I) RNA editing targets double-stranded RNA stem-loop structures in the mammalian brain. It has previously been shown that miRNAs are substrates for A-to-I editing. For the first time, we show that for several definitions of edited miRNA, the level of editing increases with development, thereby indicating a regulatory role for editing during brain maturation. We use high-throughput RNA sequencing to determine editing levels in mature miRNA, from the mouse transcriptome, and compare these with the levels of editing in pri-miRNA. We show that increased editing during development gradually changes the proportions of the two miR-376a isoforms, which previously have been shown to have different targets. Several other miRNAs that also are edited in the seed sequence show an increased level of editing through development. By comparing editing of pri-miRNA with editing and expression of the corresponding mature miRNA, we also show an editing-induced developmental regulation of miRNA expression. Taken together, our results imply that RNA editing influences the miRNA repertoire during brain maturation.
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| 4. |
- Ekdahl, Ylva, 1983-
(författare)
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A-to-I RNA editing : Function and consequences during brain development
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of my thesis has been to study how A-to-I RNA editing of miRNAs is regulated during brain development and the biological function of these editing events.Using high throughput RNA sequencing, we performed an unbiased search for edited, mature miRNAs in total mouse brain tissue from three developmental stages. We searched for known and novel editing sites within short RNA sequences approximately resembling the length of mature miRNAs.We can conclude that the gradual increase in editing efficiency seen for most selectively edited sites in transcripts encoding neurotransmission proteins, also applies to miRNAs during development of the mammalian brain. The most striking editing events all occur in the crucial seed sequence, essential for target recognition. These results indicate that A-to-I editing is utilized to diversify target recognition by the miRNAs during development.Furthermore, our data suggests that specific transcripts, targeted by either non-edited or edited miRNAs, are regulated in a manner that is consistent with the developmental shifts in editing frequencies. One example of this is the developmentally regulated editing of miR-381, targeting the Pum2 transcript in the brain. Pum2 is a translational repressor that regulates many mRNAs shown to be important for neurological functions, including memory formation and learning.We have further analyzed what determines a substrate to be edited by the ADAR enzymes, specifically in the context of the mammalian GABAA receptor. We found that long stem loop structures located close to exon sequences function as inducers of exonic editing.Taken together, my research demonstrate the power of combining, RNA-Seq, bioinformatics and specific experimental verifications in order to shed light on the impact of A-to-I editing on the process of RNA interference. Furthermore, we have expanded the knowledge of RNA structure requirements for ADAR editing to occur.
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| 5. |
- Ekdahl, Ylva, et al.
(författare)
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Complex post-transcriptional regulation of Pumilio 2 fine-tunes the neuron
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Highly polarized cells, such as differentiatedneurons, requires a sophisticated network ofregulatory events to control gene expressionin response to different environmental aswell as developmental conditions. In thisstudy we show how different RNA processingevents can work in concert to regulate geneexpression of Pumillio 2 (Pum2), atranslational repressor important forneuronal homeostasis as well as memory andlearning. We have previously shown thatmiRNAs, encoded within the miR379-410cluster, which regulate the Pum2 expressionin turn are regulated by A-to-I editing. Here,we identify an alternative splicing eventwithin the Pum2 3’UTR that facilitates theescape of targeting by many of thesemiRNAs. We propose that splicing andediting are two RNA processing events thatcan work in concert to fine-tune theexpression of Pum2 and have differenteffects depending on the neuronalsubcellular localization of the transcript.This enables a differential gene expression indifferent compartments of the cell such ascell body and synaptic buds.
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| 6. |
- Jonsson, Karin, 1980-
(författare)
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Fångna i begreppen? : Revolution, tid och politik i svensk socialistisk press 1917–1924
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis studies the uses of the concept of revolution in Swedish socialist press from 1917 to 1924. Political revolution and civil wars shook several countries. The Russian February and October Revolutions were soon followed by uprisings in countries such as Germany and Finland.While the social and political history of this period, with its mass demonstrations for bread and voting rights, often called the Swedish revolution, has been covered extensively in existing research, we know much less about the theoretical understanding of revolution among Swedish socialists. This thesis examines the concept of revolution from a perspective inspired by the Begriffsgeschichte of German historian Reinhart Koselleck. This foundation in the history of concepts aims at understanding how Swedish socialists, in a wide sense, understood their own time, how they related to the past and what they expected from the future, during the years of the First World War and the immediately following years. By focusing on what might be the most central, but also the most contested and most difficult to define, concept I hope to complement earlier research focusing on the social and political history of the period and its socialist movements.The main purpose of the thesis is to analyse how the labour movement understood revolution with particular weight placed upon the theoretical and ideological tensions between revolution and reform, determinism and voluntarism and localized and universal revolution. The starting point is the political and social changes in Sweden and abroad at that time and the place of the political press as opinion leaders capable of negotiating the space of political action. A secondary aim is to discuss how focusing on temporality can inspire new perspectives on the use of conceptual history.My research shows that how the concept of revolution was used was shaped both by already established notions regarding the socialist revolution as well as by the political situation at hand. The October Revolution forced a sharpening of its meaning, wherein different factions elaborated their understanding of it in relation to each other, which in turn determined how the concept was used fom that point on.
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