Epigenomic Landscapes of hESC-Derived Neural Rosettes: Modeling Neural Tube Formation and Diseases

Cristina Valensisi; Colin Andrus; Sam Buckberry; Naresh Doni Jayavelu; Riikka J Lund; Ryan Lister; R David Hawkins

doi:10.1016/j.celrep.2017.07.036

Epigenomic Landscapes of hESC-Derived Neural Rosettes: Modeling Neural Tube Formation and Diseases

Cell Rep. 2017 Aug 8;20(6):1448-1462. doi: 10.1016/j.celrep.2017.07.036.

Authors

Cristina Valensisi¹, Colin Andrus¹, Sam Buckberry², Naresh Doni Jayavelu³, Riikka J Lund⁴, Ryan Lister², R David Hawkins⁵

Affiliations

¹ Division of Medical Genetics, Department of Medicine and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA.
² Australian Research Council Centre of Excellence in Plant Energy Biology, School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia; Harry Perkins Institute of Medical Research, Perth, WA, Australia.
³ Division of Medical Genetics, Department of Medicine and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA; Turku Centre for Biotechnology, University of Turku, Turku, Finland.
⁴ Turku Centre for Biotechnology, University of Turku, Turku, Finland; Åbo Akademi University, Turku, Finland.
⁵ Division of Medical Genetics, Department of Medicine and Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA; Turku Centre for Biotechnology, University of Turku, Turku, Finland. Electronic address: rdhawk@uw.edu.

Abstract

We currently lack a comprehensive understanding of the mechanisms underlying neural tube formation and their contributions to neural tube defects (NTDs). Developing a model to study such a complex morphogenetic process, especially one that models human-specific aspects, is critical. Three-dimensional, human embryonic stem cell (hESC)-derived neural rosettes (NRs) provide a powerful resource for in vitro modeling of human neural tube formation. Epigenomic maps reveal enhancer elements unique to NRs relative to 2D systems. A master regulatory network illustrates that key NR properties are related to their epigenomic landscapes. We found that folate-associated DNA methylation changes were enriched within NR regulatory elements near genes involved in neural tube formation and metabolism. Our comprehensive regulatory maps offer insights into the mechanisms by which folate may prevent NTDs. Lastly, our distal regulatory maps provide a better understanding of the potential role of neurological-disorder-associated SNPs.

Keywords: DNA methylation; enhancers; epigenetics; epigenomics; neural tube defects.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
DNA Methylation
Embryonic Stem Cells / cytology*
Embryonic Stem Cells / metabolism
Enhancer Elements, Genetic
Epigenesis, Genetic*
Gene Expression Regulation, Developmental*
Gene Regulatory Networks*
Humans
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Neural Tube / embryology*
Neural Tube Defects / genetics*
Neurogenesis

Abstract

Publication types

MeSH terms

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