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Sobol, Maria
Publications (10 of 10) Show all publications
Laan, L., Klar, J., Sobol, M., Hoeber, J., Shahsavan, M., Kele, M., . . . Dahl, N. (2020). DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors. Clinical Epigenetics, 12, Article ID 9.
Open this publication in new window or tab >>DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors
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2020 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 12, article id 9Article in journal (Refereed) Published
Abstract [en]

Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages.

Results: Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling.

Conclusions: The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.

Keywords
Down syndrome, induced pluripotent stem cells, DNA-methylation, neurogenesis, transcription factors, gene expression
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-398619 (URN)10.1186/s13148-019-0803-1 (DOI)000512048300002 ()31915063 (PubMedID)
Funder
Swedish Research Council, 2015-02424The Swedish Brain Foundation, FO2018-0100The Swedish Brain Foundation, FO2019-0210Knut and Alice Wallenberg Foundation, Bioinformatic supportAstraZeneca
Available from: 2019-12-08 Created: 2019-12-08 Last updated: 2020-03-20Bibliographically approved
Schuster, J., Fatima, A., Sobol, M., Noraddin, F. H., Laan, L. & Dahl, N. (2019). Generation of three human induced pluripotent stem cell (iPSC) lines from three patients with Dravet syndrome carrying distinct SCN1A gene mutations. Stem Cell Research, 39, Article ID 101523.
Open this publication in new window or tab >>Generation of three human induced pluripotent stem cell (iPSC) lines from three patients with Dravet syndrome carrying distinct SCN1A gene mutations
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2019 (English)In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 39, article id 101523Article in journal (Refereed) Published
Abstract [en]

Dravet syndrome (DS) is a childhood epilepsy syndrome caused by heterozygous mutations in the SCN1A gene encoding voltage-gated sodium channel Nav1.1. We generated iPSCs from fibroblasts of three DS patients carrying distinct SCN1A mutations (c.5502-5509dupGCTTGAAC, c.2965G>C and c.651C>G). The iPSC lines were genetically stable and each line retained the SCN1A gene mutation of the donor fibroblasts. Characterization of the iPSC lines confirmed expression of pluripotency markers, absence of exogenous vector expression and trilineage differentiation potential. These iPSC lines offer a useful resource to investigate the molecular mechanisms underlying Nav1.1 haploinsufficiency and for drug development to improve treatment of DS patients.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398822 (URN)10.1016/j.scr.2019.101523 (DOI)000487828400037 ()31400703 (PubMedID)
Funder
Swedish Research Council, 2015-02424AstraZenecaThe Swedish Brain Foundation, FO2018-0100
Available from: 2019-12-13 Created: 2019-12-13 Last updated: 2019-12-13Bibliographically approved
Schuster, J., Sobol, M., Fatima, A., Khalfallah, A., Laan, L., Anderlid, B.-M., . . . Dahl, N. (2019). Mowat-Wilson syndrome: Generation of two human iPS cell lines (UUIGPi004A and UUIGPi005A) from siblings with a truncating ZEB2 gene variant. Stem Cell Research, 39, Article ID 101518.
Open this publication in new window or tab >>Mowat-Wilson syndrome: Generation of two human iPS cell lines (UUIGPi004A and UUIGPi005A) from siblings with a truncating ZEB2 gene variant
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2019 (English)In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 39, article id 101518Article in journal (Refereed) Published
Abstract [en]

Mowat-Wilson syndrome (MWS) is a complex developmental syndrome caused by heterozygous mutations in the Zinc finger E-box-binding homeobox 2 gene (ZEB2). We generated the first human iPSC lines from primary fibroblasts of two siblings with MWS carrying a heterozygous ZEB2 stop mutation (c.1027C > T; p.Arg343*) using the Sendai virus reprogramming system. Both iPSC lines were free from reprogramming vector genes, expressed pluripotency markers and showed potential to differentiate into the three germ layers. Genetic analysis confirmed normal karyotypes and a preserved stop mutation. These iPSC lines will provide a useful resource to study altered neural lineage fate and neuropathophysiology in MWS.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398823 (URN)10.1016/j.scr.2019.101518 (DOI)000487828400033 ()31376723 (PubMedID)
Funder
Swedish Research Council, 2015-02424The Swedish Brain Foundation, FO2018-0100
Available from: 2019-12-13 Created: 2019-12-13 Last updated: 2019-12-13Bibliographically approved
Sobol, M., Klar, J., Laan, L., Shahsavani, M., Schuster, J., Annerén, G., . . . Dahl, N. (2019). Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions. Molecular Neurobiology, 56(10), 7113-7127
Open this publication in new window or tab >>Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
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2019 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7113-7127Article in journal (Refereed) Published
Abstract [en]

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

Keywords
Down syndrome, Induced pluripotent stem cells (iPSC), Neural differentiation, RNA sequencing, Proteome profiling
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-395428 (URN)10.1007/s12035-019-1585-3 (DOI)000486010800032 ()30989628 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2015-4870Knut and Alice Wallenberg FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Swedish Brain Foundation, FO2018-0100
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-12-09Bibliographically approved
Schuster, J., Laan, L., Klar, J., Jin, Z., Huss, M., Korol, S., . . . Dahl, N. (2019). Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment. Neurobiology of Disease, 132, Article ID 104583.
Open this publication in new window or tab >>Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment
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2019 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, article id 104583Article in journal (Refereed) Published
Abstract [en]

Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. The syndrome is characterized by age related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na(v)1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic interneuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Keywords
Dravet syndrome, SCN1A, Na(v)1.1, iPSC, Neural differentiation, Neurodevelopment, Chromatin architecture
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-398427 (URN)10.1016/j.nbd.2019.104583 (DOI)000497252500015 ()31445158 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2015-02417Knut and Alice Wallenberg FoundationAstraZenecaThe Swedish Brain Foundation, FO2018-0100The Swedish Brain Foundation, FO2019-0210Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-09Bibliographically approved
Sobol, M. & Thuresson, A.-C. (2017). Delineation of the critical region for proximal deletion of chromosome 12q. Molecular Cytogenetics, 10(S1), Article ID 1.P41.
Open this publication in new window or tab >>Delineation of the critical region for proximal deletion of chromosome 12q
2017 (English)In: Molecular Cytogenetics, ISSN 1755-8166, E-ISSN 1755-8166, Vol. 10, no S1, article id 1.P41Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-346097 (URN)000410864800076 ()
Available from: 2018-03-15 Created: 2018-03-15 Last updated: 2018-03-15Bibliographically approved
Pijuan-Galito, S., Tamm, C., Schuster, J., Sobol, M., Forsberg, L. A., Merry, C. L. R. & Annerén, C. (2016). Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture. Nature Communications, 7, Article ID 12170.
Open this publication in new window or tab >>Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture
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2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 12170Article in journal (Refereed) Published
Abstract [en]

Reliable, scalable and time-efficient culture methods are required to fully realize the clinical and industrial applications of human pluripotent stem (hPS) cells. Here we present a completely defined, xeno-free medium that supports long-term propagation of hPS cells on uncoated tissue culture plastic. The medium consists of the Essential 8 (E8) formulation supplemented with inter-alpha-inhibitor (I alpha I), a human serum-derived protein, recently demonstrated to activate key pluripotency pathways in mouse PS cells. IaI efficiently induces attachment and long-term growth of both embryonic and induced hPS cell lines when added as a soluble protein to the medium at seeding. IaI supplementation efficiently supports adaptation of feeder-dependent hPS cells to xeno-free conditions, clonal growth as well as single-cell survival in the absence of Rho-associated kinase inhibitor (ROCKi). This time-efficient and simplified culture method paves the way for large-scale, high-throughput hPS cell culture, and will be valuable for both basic research and commercial applications.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-302125 (URN)10.1038/ncomms12170 (DOI)000380745900001 ()27405751 (PubMedID)
External cooperation:
Funder
Swedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceKnut and Alice Wallenberg Foundation
Available from: 2016-08-30 Created: 2016-08-30 Last updated: 2018-01-10Bibliographically approved
Sobol, M., Raykova, D., Cavelier, L., Khalfallah, A., Schuster, J. & Dahl, N. (2015). Methods of Reprogramming to Induced Pluripotent Stem Cell Associated with Chromosomal Integrity and Delineation of a Chromosome 5q Candidate Region for Growth Advantage. Stem Cells and Development, 24(17), 2032-2040
Open this publication in new window or tab >>Methods of Reprogramming to Induced Pluripotent Stem Cell Associated with Chromosomal Integrity and Delineation of a Chromosome 5q Candidate Region for Growth Advantage
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2015 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 24, no 17, p. 2032-2040Article in journal (Refereed) Published
Abstract [en]

Induced pluripotent stem cells (iPSCs) have brought great promises for disease modeling and cell-based therapies. One concern related to the use of reprogrammed somatic cells is the loss of genomic integrity and chromosome stability, a hallmark for cancer and many other human disorders. We investigated 16 human iPSC lines reprogrammed by nonintegrative Sendai virus (SeV) and another 16 iPSC lines generated by integrative lentivirus for genetic changes. At early passages we detected cytogenetic rearrangements in 44% (7/16) of iPSC lines generated by lentiviral integration whereas the corresponding figure was 6% (1/16) using SeV-based delivery. The rearrangements were numerical and/or structural with chromosomes 5 and 12 as the most frequently involved chromosomes. Three iPSC lines with chromosome 5 aberrations were derived from one and the same donor. We present in this study the aberrant karyotypes including a duplication of chromosome 5q13q33 that restricts a candidate region for growth advantage. Our results suggest that the use of integrative lentivirus confers a higher risk for cytogenetic abnormalities at early passages when compared to SeV-based reprogramming. In combination, our findings expand the knowledge on acquired cytogenetic aberrations in iPSC after reprogramming and during culture.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
urn:nbn:se:uu:diva-246225 (URN)10.1089/scd.2015.0061 (DOI)000359606100007 ()
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2017-12-04Bibliographically approved
Schuster, J., Halvardson, J., Lorenzo, L. P., Ameur, A., Sobol, M., Raykova, D., . . . Dahl, N. (2015). Transcriptome Profiling Reveals Degree of Variability in Induced Pluripotent Stem Cell Lines: Impact for Human Disease Modeling. Cellular Reprogramming, 17(5), 327-337
Open this publication in new window or tab >>Transcriptome Profiling Reveals Degree of Variability in Induced Pluripotent Stem Cell Lines: Impact for Human Disease Modeling
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2015 (English)In: Cellular Reprogramming, ISSN 2152-4971, E-ISSN 2152-4998, Vol. 17, no 5, p. 327-337Article in journal (Refereed) Published
Abstract [en]

Induced pluripotent stem cell (iPSC) technology has become an important tool for disease modeling. Insufficient data on the variability among iPSC lines derived from a single somatic parental cell line have in practice led to generation and analysis of several, usually three, iPSC sister lines from each parental cell line. We established iPSC lines from a human fibroblast line (HDF-K1) and used transcriptome sequencing to investigate the variation among three sister lines (iPSC-K1A, B, and C). For comparison, we analyzed the transcriptome of an iPSC line (iPSC-K5B) derived from a different fibroblast line (HDF-K5), a human embryonic stem cell (ESC) line (ESC-HS181), as well as the two parental fibroblast lines. All iPSC lines fulfilled stringent criteria for pluripotency. In an unbiased cluster analysis, all stem cell lines (four iPSCs and one ESC) clustered together as opposed to the parental fibroblasts. The transcriptome profiles of the three iPSC sister lines were indistinguishable from each other, and functional pathway analysis did not reveal any significant hits. In contrast, the expression profiles of the ESC line and the iPSC-K5B line were distinct from that of the sister lines iPSC-K1A, B, and C. Differentiation to embryoid bodies and subsequent analysis of germ layer markers in the five stem cell clones confirmed that the distribution of their expression profiles was retained. Taken together, our observations stress the importance of using iPSCs of different parental origin rather than several sister iPSC lines to distinguish disease-associated mechanisms from genetic background effects in disease modeling.

National Category
Other Biological Topics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-244422 (URN)10.1089/cell.2015.0009 (DOI)000361523600002 ()26348590 (PubMedID)
Funder
Swedish Research Council, K2013-66X-10829-20-3 621-2009-4629EU, European Research Council, 282330AstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish National Infrastructure for Computing (SNIC), b2013214
Available from: 2015-03-03 Created: 2015-02-16 Last updated: 2017-12-04Bibliographically approved
Klar, J., Sobol, M., Melberg, A., Mäbert, K., Ameur, A., Johansson, A. C., . . . Dahl, N. (2013). Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.. Human Mutation, 34(4), 572-577
Open this publication in new window or tab >>Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.
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2013 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 4, p. 572-577Article in journal (Refereed) Published
Abstract [en]

Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM associated haplotype followed by whole exome sequencing. Within the conserved haplotype we identified a single heterozygous mutation c.1150G>A (p.E384K) in TIA1 in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7 and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared to controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1050 years, which coincides with the epoch of early seafaring across the Baltic Sea.

National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-197333 (URN)10.1002/humu.22282 (DOI)000316629000005 ()23348830 (PubMedID)
Available from: 2013-03-22 Created: 2013-03-22 Last updated: 2017-12-06Bibliographically approved
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