Epigenetic and Transcriptional Shifts in Human Neural Stem Cells after Reprogramming into Induced Pluripotent Stem Cells and Subsequent Redifferentiation

Author:

Haubenreich Carolin1,Lenz Michael2,Schuppert Andreas2,Peitz Michael13,Koch Philipp1ORCID,Zenke Martin4567ORCID,Brüstle Oliver1ORCID

Affiliation:

1. Institute of Reconstructive Neurobiology, University of Bonn Medical Faculty and University Hospital Bonn, 53127 Bonn, Germany

2. Institute for Computational Biomedicine, RWTH Aachen University, 52074 Aachen, Germany

3. Cell Programming Core Facility, University of Bonn Medical Faculty, 53127 Bonn, Germany

4. Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, 52074 Aachen, Germany

5. Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany

6. Department of Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University Medical School, 52074 Aachen, Germany

7. Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), 52074 Aachen, Germany

Abstract

Induced pluripotent stem cells (iPSCs) and their derivatives have been described to display epigenetic memory of their founder cells, as well as de novo reprogramming-associated alterations. In order to selectively explore changes due to the reprogramming process and not to heterologous somatic memory, we devised a circular reprogramming approach where somatic stem cells are used to generate iPSCs, which are subsequently re-differentiated into their original fate. As somatic founder cells, we employed human embryonic stem cell-derived neural stem cells (NSCs) and compared them to iPSC-derived NSCs derived thereof. Global transcription profiling of this isogenic circular system revealed remarkably similar transcriptomes of both NSC populations, with the exception of 36 transcripts. Amongst these we detected a disproportionately large fraction of X chromosomal genes, all of which were upregulated in iPSC-NSCs. Concurrently, we detected differential methylation of X chromosomal sites spatially coinciding with regions harboring differentially expressed genes. While our data point to a pronounced overall reinstallation of autosomal transcriptomic and methylation signatures when a defined somatic lineage is propagated through pluripotency, they also indicate that X chromosomal genes may partially escape this reinstallation process. Considering the broad application of iPSCs in disease modeling and regenerative approaches, such reprogramming-associated alterations in X chromosomal gene expression and DNA methylation deserve particular attention.

Funder

Ministry for Innovation, Science and Research of German Federal State of North-Rhine Westphalia

BMBF

Publisher

MDPI AG

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