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Schuster, J., Klar, J., Khalfallah, A., Laan, L., Hoeber, J., Fatima, A., . . . Dahl, N. (2022). ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function. Frontiers in Molecular Neuroscience, 15, Article ID 988993.
Open this publication in new window or tab >>ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function
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2022 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 15, article id 988993Article in journal (Refereed) Published
Abstract [en]

Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2. Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.

Keywords
ZEB2, Mowat-Wilson syndrome, FOXG1, epilepsy, neurodevelopmental disease, GABAergic interneurons, transcriptional network, electrophysiology
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-212444 (URN)10.3389/fnmol.2022.988993 (DOI)000889996300001 ()36353360 (PubMedID)2-s2.0-85141439596 (Scopus ID)
Available from: 2022-12-12 Created: 2022-12-12 Last updated: 2022-12-12Bibliographically approved
Johansson, H. J., Socciarelli, F., Vacanti, N. M., Haugen, M. H., Zhu, Y., Siavelis, I., . . . Lehtiö, J. (2019). Breast cancer quantitative proteome and proteogenomic landscape. Nature Communications, 10, Article ID 1600.
Open this publication in new window or tab >>Breast cancer quantitative proteome and proteogenomic landscape
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2019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 1600Article in journal (Refereed) Published
Abstract [en]

In the preceding decades, molecular characterization has revolutionized breast cancer (BC) research and therapeutic approaches. Presented herein, an unbiased analysis of breast tumor proteomes, inclusive of 9995 proteins quantified across all tumors, for the first time recapitulates BC subtypes. Additionally, poor-prognosis basal-like and luminal B tumors are further subdivided by immune component infiltration, suggesting the current classification is incomplete. Proteome-based networks distinguish functional protein modules for breast tumor groups, with co-expression of EGFR and MET marking ductal carcinoma in situ regions of normal-like tumors and lending to a more accurate classification of this poorly defined subtype. Genes included within prognostic mRNA panels have significantly higher than average mRNA-protein correlations, and gene copy number alterations are dampened at the protein-level; underscoring the value of proteome quantification for prognostication and phenotypic classification. Furthermore, protein products mapping to non-coding genomic regions are identified; highlighting a potential new class of tumor-specific immunotherapeutic targets.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:su:diva-168347 (URN)10.1038/s41467-019-09018-y (DOI)000463695400015 ()30962452 (PubMedID)2-s2.0-85064079271 (Scopus ID)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2023-03-28Bibliographically approved
Lundmark, A., Hu, Y. O. O., Huss, M., Johannsen, G., Andersson, A. F. & Yucel-Lindberg, T. (2019). Identification of Salivary Microbiota and Its Association With Host Inflammatory Mediators in Periodontitis. Frontiers in Cellular and Infection Microbiology, 9, Article ID 216.
Open this publication in new window or tab >>Identification of Salivary Microbiota and Its Association With Host Inflammatory Mediators in Periodontitis
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2019 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 9, article id 216Article in journal (Refereed) Published
Abstract [en]

Periodontitis is a microbial-induced chronic inflammatory disease, which may not only result in tooth loss, but can also contribute to the development of various systemic diseases. The transition from healthy to diseased periodontium depends on microbial dysbiosis and impaired host immune response. Although periodontitis is a common disease as well as associated with various systemic inflammatory conditions, the taxonomic profiling of the salivary microbiota in periodontitis and its association with host immune and inflammatory mediators has not been reported. Therefore, the aim of this study was to identify key pathogens and their potential interaction with the host's inflammatory mediators in saliva samples for periodontitis risk assessment. The microbial 16S rRNA gene sequencing and the levels of inflammatory mediators were performed in saliva samples from patients with chronic periodontitis and periodontally healthy control subjects. The salivary microbial community composition differed significantly between patients with chronic periodontitis and healthy controls. Our analyses identified a number of microbes, including bacteria assigned to Eubacterium saphenum, Tannerella forsythia, Filifactor alocis, Streptococcus mitis/parasanguinis, Parvimonas micra, Prevotella sp., Phocaeicola sp., and Fretibacterium sp. as more abundant in periodontitis, compared to healthy controls. In samples from healthy individuals, we identified Campylobacter concisus, and Veillonella sp. as more abundant. Integrative analysis of the microbiota and inflammatory mediators/cytokines revealed associations that included positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6R alpha, sTNF-R1, and gp 130/sIL-6R beta. In addition, a negative correlation was identified between IL-10 and Filifactor alocis. Our results reveal distinct and disease-specific patterns of salivary microbial composition between patients with periodontitis and healthy controls, as well as significant correlations between microbiota and host-mediated inflammatory cytokines. The positive correlations between the pathogens Treponema sp. and Selenomas sp. and the cytokines chitinase 3-like 1, sIL-6R alpha, sTNF-R1, and gp 130/sIL-6R beta might have the future potential to serve as a combined bacteria-host salivary biomarker panel for diagnosis of the chronic infectious disease periodontitis. However, further studies are required to determine the capacity of these microbes and inflammatory mediators as a salivary biomarker panel for periodontitis.

Keywords
16S rRNA sequencing, cytokines, inflammatory mediators, microbiome, microbiota, periodontitis, saliva
National Category
Biological Sciences Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-171107 (URN)10.3389/fcimb.2019.00216 (DOI)000472529100001 ()31281801 (PubMedID)
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2022-03-23Bibliographically 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:su:diva-175029 (URN)10.1007/s12035-019-1585-3 (DOI)000486010800032 ()30989628 (PubMedID)
Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2022-03-23Bibliographically 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.

Keywords
Dravet syndrome, SCN1A, Na(v)1.1, iPSC, Neural differentiation, Neurodevelopment, Chromatin architecture
National Category
Neurosciences Biological Sciences
Identifiers
urn:nbn:se:su:diva-176668 (URN)10.1016/j.nbd.2019.104583 (DOI)000497252500015 ()31445158 (PubMedID)
Available from: 2019-12-17 Created: 2019-12-17 Last updated: 2022-03-23Bibliographically approved
Zhu, Y., Orre, L. M., Johansson, H. J., Huss, M., Boekel, J., Vesterlund, M., . . . Lehtiö, J. (2018). Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow. Nature Communications, 9, Article ID 903.
Open this publication in new window or tab >>Discovery of coding regions in the human genome by integrated proteogenomics analysis workflow
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2018 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 9, article id 903Article in journal (Refereed) Published
Abstract [en]

Proteogenomics enable the discovery of novel peptides (from unannotated genomic protein-coding loci) and single amino acid variant peptides (derived from single-nucleotide polymorphisms and mutations). Increasing the reliability of these identifications is crucial to ensure their usefulness for genome annotation and potential application as neoantigens in cancer immunotherapy. We here present integrated proteogenomics analysis workflow (IPAW), which combines peptide discovery, curation, and validation. IPAW includes the SpectrumAI tool for automated inspection of MS/MS spectra, eliminating false identifications of single-residue substitution peptides. We employ IPAW to analyze two proteomics data sets acquired from A431 cells and five normal human tissues using extended (pH range, 3-10) high-resolution isoelectric focusing (HiRIEF) pre-fractionation and TMT-based peptide quantitation. The IPAW results provide evidence for the translation of pseudogenes, lncRNAs, short ORFs, alternative ORFs, N-terminal extensions, and intronic sequences. Moreover, our quantitative analysis indicates that protein production from certain pseudogenes and lncRNAs is tissue specific.

National Category
Biological Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:su:diva-154630 (URN)10.1038/s41467-018-03311-y (DOI)000426469900005 ()29500430 (PubMedID)
Available from: 2018-04-03 Created: 2018-04-03 Last updated: 2023-12-04Bibliographically approved
James, T., Lindén, M., Morikawa, H., Fernandes, S. J., Ruhrmann, S., Huss, M., . . . Kockum, I. (2018). Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients. Human Molecular Genetics, 27(5), 912-928
Open this publication in new window or tab >>Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 5, p. 912-928Article in journal (Refereed) Published
Abstract [en]

Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as multiple sclerosis (MS). As a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells from MS patients (n = 145) to identify eQTLs in regions centered on 109 MS risk single nucleotide polymorphisms and 7 associated human leukocyte antigen variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalized with the disease association signal. As many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major peripheral blood mononuclear cell-derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared with non-inflammatory neurological diseases patients. In addition, we found two single nucleotide polymorphisms to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-154802 (URN)10.1093/hmg/ddy001 (DOI)000426838200012 ()29325110 (PubMedID)
Available from: 2018-04-13 Created: 2018-04-13 Last updated: 2022-02-26Bibliographically approved
Troell, K., Hallström, B., Divne, A.-M., Alsmark, C., Arrighi, R., Huss, M., . . . Bertilsson, S. (2016). Cryptosporidium as a testbed for single cell genome characterization of unicellular eukaryotes. BMC Genomics, 17, Article ID 471.
Open this publication in new window or tab >>Cryptosporidium as a testbed for single cell genome characterization of unicellular eukaryotes
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2016 (English)In: BMC Genomics, E-ISSN 1471-2164, Vol. 17, article id 471Article in journal (Refereed) Published
Abstract [en]

Background: Infectious disease involving multiple genetically distinct populations of pathogens is frequently concurrent, but difficult to detect or describe with current routine methodology. Cryptosporidium sp. is a widespread gastrointestinal protozoan of global significance in both animals and humans. It cannot be easily maintained in culture and infections of multiple strains have been reported. To explore the potential use of single cell genomics methodology for revealing genome-level variation in clinical samples from Cryptosporidium-infected hosts, we sorted individual oocysts for subsequent genome amplification and full-genome sequencing. Results: Cells were identified with fluorescent antibodies with an 80 % success rate for the entire single cell genomics workflow, demonstrating that the methodology can be applied directly to purified fecal samples. Ten amplified genomes from sorted single cells were selected for genome sequencing and compared both to the original population and a reference genome in order to evaluate the accuracy and performance of the method. Single cell genome coverage was on average 81 % even with a moderate sequencing effort and by combining the 10 single cell genomes, the full genome was accounted for. By a comparison to the original sample, biological variation could be distinguished and separated from noise introduced in the amplification. Conclusions: As a proof of principle, we have demonstrated the power of applying single cell genomics to dissect infectious disease caused by closely related parasite species or subtypes. The workflow can easily be expanded and adapted to target other protozoans, and potential applications include mapping genome-encoded traits, virulence, pathogenicity, host specificity and resistance at the level of cells as truly meaningful biological units.

Keywords
Apicomplexa, Single cell genomics, Whole genome amplification, Cryptosporidium, Multiple infection, FACS
National Category
Environmental Biotechnology Biological Sciences
Identifiers
urn:nbn:se:su:diva-132396 (URN)10.1186/s12864-016-2815-y (DOI)000378380600001 ()27338614 (PubMedID)
Available from: 2016-08-15 Created: 2016-08-11 Last updated: 2024-01-17Bibliographically approved
Hagey, D. W., Zaouter, C., Combeau, G., Andersson Lendahl, M., Andersson, O., Huss, M. & Muhr, J. (2016). Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells. Genome Research, 26(7), 908-917
Open this publication in new window or tab >>Distinct transcription factor complexes act on a permissive chromatin landscape to establish regionalized gene expression in CNS stem cells
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2016 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, no 7, p. 908-917Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Biochemistry and Molecular Biology Environmental Biotechnology
Identifiers
urn:nbn:se:su:diva-132561 (URN)10.1101/gr.203513.115 (DOI)000378986000005 ()27197220 (PubMedID)
Available from: 2016-08-16 Created: 2016-08-15 Last updated: 2022-03-23Bibliographically approved
Ma, Y., Miao, Y., Peng, Z., Sandgren, J., De Stahl, T. D., Huss, M., . . . Li, C. (2016). Identification of mutations, gene expression changes and fusion transcripts by whole transcriptome RNAseq in docetaxel resistant prostate cancer cells. SpringerPlus, 5, Article ID 1861.
Open this publication in new window or tab >>Identification of mutations, gene expression changes and fusion transcripts by whole transcriptome RNAseq in docetaxel resistant prostate cancer cells
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2016 (English)In: SpringerPlus, E-ISSN 2193-1801, Vol. 5, article id 1861Article in journal (Refereed) Published
Abstract [en]

Docetaxel has been the standard first-line therapy in metastatic castration resistant prostate cancer. The survival benefit is, however, limited by either primary or acquired resistance. In this study, Du145 prostate cancer cells were converted to docetaxel-resistant cells Du145-R and Du145-RB by in vitro culturing. Next generation RNAseq was employed to analyze these cell lines. Forty-two genes were identified to have acquired mutations after the resistance development, of which thirty-four were found to have mutations in published sequencing studies using prostate cancer samples from patients. Fourteen novel and 2 previously known fusion genes were inferred from the RNA-seq data, and 13 of these were validated by RT-PCR and/or re-sequencing. Four in-frame fusion transcripts could be transcribed into fusion proteins in stably transfected HEK293 cells, including MYH9-EIF3D and LDLR-RPL31P11, which were specific identified or up-regulated in the docetaxel resistant DU145 cells. A panel of 615 gene transcripts was identified to have significantly changed expression profile in the docetaxel resistant cells. These transcriptional changes have potential for further study as predictive biomarkers and as targets of docetaxel treatment.

Keywords
Docetaxel resistance, Prostate cancer, RNAseq, Gene fusion, Mutation, Altered expression
National Category
Biological Sciences Cancer and Oncology
Identifiers
urn:nbn:se:su:diva-137516 (URN)10.1186/s40064-016-3543-0 (DOI)000390007800001 ()27822437 (PubMedID)
Available from: 2017-01-18 Created: 2017-01-09 Last updated: 2023-06-13Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0839-2451

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