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  • 1.
    Bergqvist, Cecilia
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Niss, Frida
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Figueroa, Ricardo A.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Beckman, Marie
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Karolinska Institutet, Sweden.
    Maksel, Danuta
    Jafferali, Mohammed H.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kulyté, Agné
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hallberg, Einar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Monitoring of chromatin organization in live cells by FRIC. Effects of the inner nuclear membrane protein Samp12019In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 47, no 9, article id e49Article in journal (Refereed)
    Abstract [en]

    In most cells, transcriptionally inactive heterochromatin is preferentially localized in the nuclear periphery and transcriptionally active euchromatin is localized in the nuclear interior. Different cell types display characteristic chromatin distribution patterns, which change dramatically during cell differentiation, proliferation, senescence and different pathological conditions. Chromatin organization has been extensively studied on a cell population level, but there is a need to understand dynamic reorganization of chromatin at the single cell level, especially in live cells. We have developed a novel image analysis tool that we term Fluorescence Ratiometric Imaging of Chromatin (FRIC) to quantitatively monitor dynamic spatiotemporal distribution of euchromatin and total chromatin in live cells. A vector (pTandemH) assures stoichiometrically constant expression of the histone variants Histone 3.3 and Histone 2B, fused to EGFP and mCherry, respectively. Quantitative ratiometric (H3.3/H2B) imaging displayed a concentrated distribution of heterochromatin in the periphery of U2OS cell nuclei. As proof of concept, peripheral heterochromatin responded to experimental manipulation of histone acetylation. We also found that peripheral heterochromatin depended on the levels of the inner nuclear membrane protein Samp1, suggesting an important role in promoting peripheral heterochromatin. Taken together, FRIC is a powerful and robust new tool to study dynamic chromatin redistribution in live cells.

  • 2.
    Niss, Frida
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    RNA binding proteins and epigenetics in SCA72019Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Polyglutamine diseases are a group of nine disorders that includes, among others SCA7. The common denominator is an expanded glutamine tract in the respective disease protein caused by unstable replication during meiosis. Most research within this field points to a combination of gain-of-function and loss-of-function mechanisms causing all polyglutamine diseases. Using a SCA7 model we are thus attempting to study both of these mechanisms. The glutamine tract expansion responsible for SCA7 is located in the protein Ataxin-7, which like the other polyglutamine proteins aggregates into large inclusions in patient cells. In a gain-of-function mechanism, the aggregates are suggested to cause stress to the cell by e.g. sequestering vital proteins into the aggregates, which could disrupt their function. RNA-binding proteins such as FUS and TDP-43 are often found in aggregates in neurodegenerative diseases, and have been observed in SCA7 aggregates as well. However, if disruption of FUS and TDP-43 function occurs, or if it plays a role in SCA7 pathology is unclear. We found a high rate of co-aggregation of FUS with Ataxin-7 using immunofluorescence and filter trap assays. Furthermore, we found that both the localization and function of FUS was altered in a SCA7 cell model using cell fractionations and RT-PCR. Additionally, we found that TDP-43 also co-aggregated with Ataxin-7 and phosphorylation of TDP-43 was increased during the disease phenotype.

    Wild-type Ataxin-7 normally functions within chromatin regulation processes, and loss-of-function pathology in SCA7 could therefore involve a disruption of these processes. We have developed a method, FRIC, that enables us to study chromatin organization in live cells using confocal microscopy and fluorescently tagged histones. Using inhibitors of HATs and HDACs, as well as a previously known protein that regulates chromatin structure, we were able to observe changes in chromatin structure in the nuclear periphery, confirming the usefulness of FRIC. Additionally, we investigated the involvement of an inner nuclear membrane protein, Samp1, in chromatin organization and found Samp1 to be instrumental in organizing peripheral chromatin.

    Taken together, the results from these two studies indicate that SCA7 pathology disturbs RNA-binding protein mediated transcriptional regulation in a gain-of-function mechanism, and that FRIC is a powerful new tool for examining chromatin regulation in diseases with disrupted transcription, like SCA7.

  • 3.
    Niss, Frida
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Zaidi, Wajiha
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Papadopoulou, Elisavet
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hallberg, Einar
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ström, Anna-Lena
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Polyglutamine expanded Ataxin-7 alters FUS localization and function in a SCA7 cell modelManuscript (preprint) (Other academic)
    Abstract [en]

    Polyglutamine (polyQ) diseases, such as Spinocerebellar ataxia type 7, are caused by the expansion of a CAG/polyglutamine repeat in a disease specific gene/protein. Misfolding and aggregation of the expanded protein can be observed in all polyQ disorders and sequestration of vital proteins into the aggregates formed have been suggested as a common pathological mechanism. FUS, an RNA binding protein, is frequently observed in polyglutamine aggregates. However, whether or not FUS disruption contributes to polyQ pathology is not clear.

    To address this question we used confocal microscopy, cell fractionation, filter traps and western blot, to study how FUS localization and function is affected by the SCA7 disease protein ataxin-7 (ATXN7). We found that aggregates formed by polyQ expanded ATXN7 were to a high degree also FUS positive and FUS re-distributed into the insoluble cell fraction together with mutant ATXN7. Moreover, a shift in abundance of FUS from the nucleus to the cytoplasm was observed and associated with altered levels of FUS regulated mRNAs in mutant ATXN7 expressing cells. However, some of the affected mRNAs are also regulated by the RNA binding protein TDP-43, which we could also show co-localized with ATXN7 aggregates using microscopy. Moreover, increased phosphorylation of serine 409/410 in TDP-43, which has been linked to TDP-43 neurotoxicity, could be observed in mutant ATXN7 expressing cells. Taken together, these findings lead us to conclude that disruption of FUS and also TDP-43 could potentially play a role in SCA7 pathology.

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