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DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.ORCID iD: 0000-0003-4185-7409
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.ORCID iD: 0000-0001-5602-0850
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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.

Place, publisher, year, edition, pages
2020. Vol. 12, article id 9
Keywords [en]
Down syndrome, induced pluripotent stem cells, DNA-methylation, neurogenesis, transcription factors, gene expression
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-398619DOI: 10.1186/s13148-019-0803-1ISI: 000512048300002PubMedID: 31915063OAI: oai:DiVA.org:uu-398619DiVA, id: diva2:1376148
Funder
Swedish Research Council, 2015-02424The Swedish Brain Foundation, FO2018-0100The Swedish Brain Foundation, FO2019-0210Knut and Alice Wallenberg Foundation, Bioinformatic supportAstraZenecaAvailable from: 2019-12-08 Created: 2019-12-08 Last updated: 2020-03-20Bibliographically approved
In thesis
1. Induced pluripotent stem cell (iPSC) modelling for the identification of mechanisms behind neurodevelopmental disorders
Open this publication in new window or tab >>Induced pluripotent stem cell (iPSC) modelling for the identification of mechanisms behind neurodevelopmental disorders
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human induced pluripotent stem cells (iPSCs) have opened new possibilities to recapitulate disease mechanisms and to model disorders in vitro. In the studies presented here, iPSCs were established to model neural differentiation in Down syndrome (DS), caused by trisomy for chromosome 21 (T21); Dravet syndrome (DRS), caused by variants in the SCN1A gene; and an ataxia syndrome, caused by a variant in the NFASC gene. The major aim has been to uncover molecular and cellular mechanisms behind perturbed neurogenesis in the three disorders.

In Paper I, the analysis of transcriptomes and proteomes of the DS iPSC derived neural model revealed several perturbed gene clusters with strong temporal dynamics along neural differentiation, markedly down-regulated mitochondrial genes and a dysregulation of hub proteins. These results predict complex and genome-wide changes in T21 neural cells associated with prolonged cell cycle, reduced cell growth and a perturbed energy metabolism.

In Paper II, it was demonstrated that the transcriptional profile of iPSC based neural model system for DS was enriched for differentially methylated genes and gene families when compared to a corresponding euploid model. The differentially methylated genes were enriched for transcriptional regulation and chromatin structure, suggesting novel mechanistic links between the genomic imbalance caused by T21 and the global transcriptional dysregulation in DS.

 In Paper III, it was shown that DRS patient iPSCs differentiated into GABAergic interneurons exhibit a dysregulated epilepsy gene network as well as an altered expression of genes involved in chromatin remodelling, accompanied by abnormal electrophysiological properties and increased stress sensitivity.

In Paper IV, it was shown that neural iPSCs, established from a patient with an ataxia syndrome and a novel homozygous variant in the NFASC gene, lack a full-length neurofascin-186 important for cell adhesion. The patient derived neural iPSCs showed delayed neuronal differentiation, reduced sprouting, shorter neurites and altered electrophysiology.

The Papers I-IV show that patient derived neural iPSCs enable to identify molecular and cellular mechanisms associated with neuropathogenesis. Besides specific dysregulated pathways and cellular defects in models of three developmental disorders, with shortlists of novel candidate disease biomarkers, the results are consistent with prior data and clinical presentation of patients. The knowledge gained is of paramount importance for translation into clinical settings and a step towards development of novel therapies with the ultimate goal to alleviate symptoms of affected individuals.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 63
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1622
Keywords
Induced pluripotent stem cells, Neurogenesis, Neural differentiation, Down syndrome, Dravet syndrome, Ataxia
National Category
Medical and Health Sciences
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-398620 (URN)978-91-513-0833-3 (ISBN)
Public defence
2020-02-07, Room A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2020-01-17 Created: 2019-12-09 Last updated: 2020-03-05

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