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  • 16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development.

16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development.

eLife (2020-11-11)
Julien G Roth, Kristin L Muench, Aditya Asokan, Victoria M Mallett, Hui Gai, Yogendra Verma, Stephen Weber, Carol Charlton, Jonas L Fowler, Kyle M Loh, Ricardo E Dolmetsch, Theo D Palmer
ABSTRACT

Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of 'footprint'-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information-available with the cell lines by request from the Simons Foundation Autism Research Initiative-with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cell Dissociation Solution Non-enzymatic 1x, Prepared in phosphate buffered saline without calcium and magnesium, sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
2-Mercaptoethanol, ≥99.0%
Sigma-Aldrich
Poly-D-lysine hydrobromide, average mol wt 30,000-70,000, lyophilized powder, γ-irradiated, BioReagent, suitable for cell culture
Sigma-Aldrich
Poly-D-lysine hydrobromide, mol wt ≥300,000
Roche
Laminin, from mouse Engelbreth-Holm-Swarm (EHS) sarcoma