| 1. |
- Kurtsdotter, Idha, et al.
(författare)
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SOX5/6/21 prevent oncogene-driven transformation of brain stem cells
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:18, s. 4985-4997
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Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult.
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| 2. |
- Hagey, Daniel W., et al.
(författare)
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Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells
- 2016
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 26:7, s. 908-917
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Tidskriftsartikel (refereegranskat)abstract
- Spatially distinct gene expression profiles in neural stem cells (NSCs) are a prerequisite to the formation of neuronal diversity, but how these arise from the regulatory interactions between chromatin accessibility and transcription factor activity has remained unclear. Here, we demonstrate that, despite their distinct gene expression profiles, NSCs of the mouse cortex and spinal cord share the majority of their DNase I hypersensitive sites (DHSs). Regardless of this similarity, domain-specific gene expression is highly correlated with the relative accessibility of associated DHSs, as determined by sequence read density. Notably, the binding pattern of the general NSC transcription factor SOX2 is also largely cell type specific and coincides with an enrichment of LHX2 motifs in the cortex and HOXA9 motifs in the spinal cord. Interestingly, in a zebrafish reporter gene system, these motifs were critical determinants of patterned gene expression along the rostral-caudal axis. Our findings establish a predictive model for patterned NSC gene expression, whereby domain-specific expression of LHX2 and HOX proteins act on their target motifs within commonly accessible cis-regulatory regions to specify SOX2 binding. In turn, this binding correlates strongly with these DHSs relative accessibility-a robust predictor of neighboring gene expression.
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| 3. |
- Hagey, Daniel W
(författare)
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Transcriptional regulation of development in time and space
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human development requires the generation of trillions of cells with myriad functions from a single cell. This requires that restriction of stem cell fate competence and proliferation are precisely temporally and spatially patterned as the embryo grows. To accomplish this, the chromatin landscape of individual stem cells progressively constrains gene expression in a context specific manner in order to guide cell behavior. In turn, this context is provided by the cellular environment and intrinsic determinants via the activity of transcription factors. In paper I, we utilize ChIP-sequencing to study the overlapping and specific activities of the transcription factor sex determining region Y-box 2 (SOX2) in the developing cortex, spinal cord, stomach and lungs. We show that cell type specific binding is associated with tissue specific gene expression, while commonly bound cis-regulatory modules neighbor genes involved in the core processes of stem cell maintenance and proliferation. In paper II, we use DNase- and ChIP-sequencing to demonstrate that, though the accessible chromatin landscape in the spinal cord and cortex are highly overlapping, SOX2 binding is primarily specific to one region. We find that this is due to an association with the specifically expressed partner transcription factors HOXA9 in spinal cord and LHX2 in cortex, which are capable of respecifying gene expression when misexpressed. In paper III, we exploit single cell RNA-sequencing to establish that the stem cell population of the early cortex expresses high levels of S o x2, exhibits features of multipotency, and is enriched for genes involved in mitosis, such as Ccnb1/2. In contrast, the committed progenitor pool expresses high levels of the G1/S-phase genes, including Ccnd1, which is capable of inducing differentiation when overexpressed. In paper IV, we find that Sox2 acts in a dose-dependent fashion to control proliferation in the developing cortex by directly repressing Ccnd1. We show that this is accomplished via the binding of off-consensus sites in the Ccnd1 promoter, and an association with Wnt signal transducing, TCF/LEF, transcription factors and their established co-repressor, TLE1.
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| 4. |
- Klum, Susanne, et al.
(författare)
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Sequentially acting SOX proteins orchestrate astrocyte- and oligodendrocyte-specific gene expression
- 2018
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Ingår i: EMBO Reports. - : WILEY. - 1469-221X .- 1469-3178. ; 19:11
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Tidskriftsartikel (refereegranskat)abstract
- SOX transcription factors have important roles during astrocyte and oligodendrocyte development, but how glial genes are specified and activated in a sub-lineage-specific fashion remains unknown. Here, we define glial-specific gene expression in the developing spinal cord using single-cell RNA-sequencing. Moreover, by ChIP-seq analyses we show that these glial gene sets are extensively preselected already in multipotent neural precursor cells through prebinding by SOX3. In the subsequent lineage-restricted glial precursor cells, astrocyte genes become additionally targeted by SOX9 at DNA regions strongly enriched for Nfi binding motifs. Oligodendrocyte genes instead are prebound by SOX9 only, at sites which during oligodendrocyte maturation are targeted by SOX10. Interestingly, reporter gene assays and functional studies in the spinal cord reveal that SOX3 binding represses the synergistic activation of astrocyte genes by SOX9 and NFIA, whereas oligodendrocyte genes are activated in a combinatorial manner by SOX9 and SOX10. These genome-wide studies demonstrate how sequentially expressed SOX proteins act on lineage-specific regulatory DNA elements to coordinate glial gene expression both in a temporal and in a sub-lineage-specific fashion.
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| 5. |
- Visnes, Torkild, et al.
(författare)
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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress
- 2020
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 48:21, s. 12234-12251
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Tidskriftsartikel (refereegranskat)abstract
- Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.
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