Long Non-Coding RNAs as Surrogate Indicators for Chemical Stress Responses in Human-Induced Pluripotent Stem Cells

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Abstract

In this study, we focused on two biological products as ideal tools for toxicological assessment: long non-coding RNAs (lncRNAs) and human-induced pluripotent stem cells (hiPSCs). lncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to cellular stresses. hiPSCs possess the capabilities of self-renewal and differentiation into multiple cell types, and they are free of the ethical issues associated with human embryonic stem cells. Here, we identified six novel lncRNAs (CDKN2B-AS1, MIR22HG, GABPB1-AS1, FLJ33630, LINC00152, and LINC0541471_v2) that respond to model chemical stresses (cycloheximide, hydrogen peroxide, cadmium, or arsenic) in hiPSCs. Our results indicated that the lncRNAs responded to general and specific chemical stresses. Compared with typical mRNAs such as p53-related mRNAs, the lncRNAs highly and rapidly responded to chemical stresses. We propose that these lncRNAs have the potential to be surrogate indicators of chemical stress responses in hiPSCs.

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Reprogramming of human somatic cells to pluripotency with defined factors.

In-Hyun Park, Rui Zhao, Jason A. West … (2008)

Pluripotency pertains to the cells of early embryos that can generate all of the tissues in the organism. Embryonic stem cells are embryo-derived cell lines that retain pluripotency and represent invaluable tools for research into the mechanisms of tissue formation. Recently, murine fibroblasts have been reprogrammed directly to pluripotency by ectopic expression of four transcription factors (Oct4, Sox2, Klf4 and Myc) to yield induced pluripotent stem (iPS) cells. Using these same factors, we have derived iPS cells from fetal, neonatal and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. These data demonstrate that defined factors can reprogramme human cells to pluripotency, and establish a method whereby patient-specific cells might be established in culture.

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Generation of human induced pluripotent stem cells from dermal fibroblasts.

W. E. Lowry, L. Richter, R Yachechko … (2008)

The generation of patient-specific pluripotent stem cells has the potential to accelerate the implementation of stem cells for clinical treatment of degenerative diseases. Technologies including somatic cell nuclear transfer and cell fusion might generate such cells but are hindered by issues that might prevent them from being used clinically. Here, we describe methods to use dermal fibroblasts easily obtained from an individual human to generate human induced pluripotent stem (iPS) cells by ectopic expression of the defined transcription factors KLF4, OCT4, SOX2, and C-MYC. The resultant cell lines are morphologically indistinguishable from human embryonic stem cells (HESC) generated from the inner cell mass of a human preimplantation embryo. Consistent with these observations, human iPS cells share a nearly identical gene-expression profile with two established HESC lines. Importantly, DNA fingerprinting indicates that the human iPS cells were derived from the donor material and are not a result of contamination. Karyotypic analyses demonstrate that reprogramming of human cells by defined factors does not induce, or require, chromosomal abnormalities. Finally, we provide evidence that human iPS cells can be induced to differentiate along lineages representative of the three embryonic germ layers indicating the pluripotency of these cells. Our findings are an important step toward manipulating somatic human cells to generate an unlimited supply of patient-specific pluripotent stem cells. In the future, the use of defined factors to change cell fate may be the key to routine nuclear reprogramming of human somatic cells.

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Is Open Access

Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals

Hidenori Tani, Rena Mizutani, Kazi Abdus Salam … (2012)

Mammalian genomes produce huge numbers of noncoding RNAs (ncRNAs). However, the functions of most ncRNAs are unclear, and novel techniques that can distinguish functional ncRNAs are needed. Studies of mRNAs have revealed that the half-life of each mRNA is closely related to its physiological function, raising the possibility that the RNA stability of an ncRNA reflects its function. In this study, we first determined the half-lives of 11,052 mRNAs and 1418 ncRNAs in HeLa Tet-off (TO) cells by developing a novel genome-wide method, which we named 5′- br omo-uridine i mmunoprecipitation c hase–deep sequencing analysis (BRIC-seq). This method involved pulse-labeling endogenous RNAs with 5′-bromo-uridine and measuring the ongoing decrease in RNA levels over time using multifaceted deep sequencing. By analyzing the relationship between RNA half-lives and functional categories, we found that RNAs with a long half-life ( t 1/2 ≥ 4 h) contained a significant proportion of ncRNAs, as well as mRNAs involved in housekeeping functions, whereas RNAs with a short half-life ( t 1/2 < 4 h) included known regulatory ncRNAs and regulatory mRNAs. The stabilities of a significant set of short-lived ncRNAs are regulated by external stimuli, such as retinoic acid treatment. In particular, we identified and characterized several novel long ncRNAs involved in cell proliferation from the group of short-lived ncRNAs. We designated this novel class of ncRNAs with a short half-life as S hort- Li ved noncoding T ranscripts (SLiTs). We propose that the strategy of monitoring RNA half-life will provide a powerful tool for investigating hitherto functionally uncharacterized regulatory RNAs.

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Author and article information

Contributors

Atsushi Asakura: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 29 August 2014

Volume: 9

Issue: 8

Electronic Location Identifier: e106282

Affiliations

[1 ]Research Institute for Environmental Management Technology, National Institute of Advanced Industrial Science and Technology (AIST), 16-1, Onogawa, Tsukuba, Ibaraki, Japan

[2 ]Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki, Japan

University of Minnesota Medical School, United States of America

Author notes

* E-mail: h.tani@ 123456aist.go.jp

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: HT YO YI MT. Performed the experiments: HT YO. Analyzed the data: HT. Contributed to the writing of the manuscript: HT YO YI MT.

Article

Publisher ID: PONE-D-14-17808

DOI: 10.1371/journal.pone.0106282

PMC ID: 4149554

PubMed ID: 25171338

SO-VID: 78e8fcd4-dfcd-42c6-a78a-dcc65543868a

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 23 April 2014

Date accepted : 3 August 2014

Page count

Pages: 6

Funding

The authors have no funding or support to report.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are included within the paper.

Long Non-Coding RNAs as Surrogate Indicators for Chemical Stress Responses in Human-Induced Pluripotent Stem Cells

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Abstract

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Stress signalling in stem cells

Most cited references 10

Reprogramming of human somatic cells to pluripotency with defined factors.

Generation of human induced pluripotent stem cells from dermal fibroblasts.

Genome-wide determination of RNA stability reveals hundreds of short-lived noncoding transcripts in mammals

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