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Toxicol Sci. 2017 Sep 1;159(1):251-265. doi: 10.1093/toxsci/kfx129.

RNA-Seq of Human Neural Progenitor Cells Exposed to Lead (Pb) Reveals Transcriptome Dynamics, Splicing Alterations and Disease Risk Associations.

Author information

1
Regenerative Biology Laboratory, Morgridge Institute for Research, Madison, Wisconsin 53707.
2
Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin 53706.
3
Department of Molecular Cellular and Developmental Biology, University of California, Santa Barbara, California 93106.

Abstract

Lead (Pb) is a well-known toxicant, especially for the developing nervous system, albeit the mechanism is largely unknown. In this study, we use time series RNA-seq to conduct a genome-wide survey of the transcriptome response of human embryonic stem cell-derived neural progenitor cells to lead treatment. Using a dynamic time warping algorithm coupled with statistical tests, we find that lead can either accelerate or decelerate the expression of specific genes during the time series. We further show that lead disrupts a neuron- and brain-specific splicing factor NOVA1 regulated splicing network. Using lead induced transcriptome change signatures, we predict several known and novel disease risks under lead exposure. The findings in this study will allow a better understanding of the mechanism of lead toxicity, facilitate the development of diagnostic biomarkers and treatment for lead exposure, and comprise a highly valuable resource for environmental toxicology. Our study also demonstrates that a human (embryonic stem) cell-derived system can be used for studying the mechanism of toxicants, which can be useful for drug or compound toxicity screens and safety assessment.

KEYWORDS:

RNA-seq; disease risk prediction; dynamic time warping; lead (Pb) exposure; time series; transcriptome response

PMID:
28903495
PMCID:
PMC6372217
DOI:
10.1093/toxsci/kfx129
[Indexed for MEDLINE]
Free PMC Article

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