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A Genome-Wide Analysis of the Gene Expression and Alternative Splicing Events in a Whole-Body Hypoxic Preconditioning Mouse Model

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Abstract

Exposure to specific doses of hypoxia can trigger endogenous neuroprotective and neuroplastic mechanisms of the central nervous system. These molecular mechanisms, together referred to as hypoxic preconditioning (HPC), remain poorly understood. In the present study, we applied RNA sequencing and bioinformatics analyses to study HPC in a whole-body HPC mouse model. The preconditioned (H4) and control (H0) groups showed 605 differentially expressed genes (DEGs), of which 263 were upregulated and 342 were downregulated. Gene Ontology enrichment analysis indicated that these DEGs were enriched in several biological processes, including metabolic stress and angiogenesis. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that the FOXO and Notch signaling pathways were involved in hypoxic tolerance and protection during HPC. Furthermore, 117 differential alternative splicing events (DASEs) were identified, with exon skipping being the dominant one (48.51%). Repeated exposure to systemic hypoxia promoted skipping of exon 7 in Edrf1 and exon 9 or 13 in Lrrc45. This study expands the understanding of the endogenous protective mechanisms of HPC and the DASEs that occur during HPC.

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Abbreviations

AS:

Alternative splicing

A5SS:

Alternative 5′splice sites

A3SS:

Alternative 3′splice sites

DASEs:

Differentially alternative splicing events

DEGs:

Differentially expressed genes

GO:

Gene Ontology

HE:

Hematoxylin-eosin

HPC:

Hypoxic preconditioning

IR:

Intron retention

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MDA:

Malondialdehyde

MXE:

Mutually exclusive exon

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

RNA-seq:

RNA sequencing

ROS:

Reactive oxygen species

SE:

Skipped exons

SOD:

Superoxide dismutase

SoHPC:

Single-organ hypoxic preconditioning

WbHPC:

Whole-body hypoxic preconditioning

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Acknowledgements

We wish to thank Prof. L Cai and ZW Yan for her invaluable advice and support in the preparation of this work.

Funding

The study was carried out by the funds received by National Natural Science Foundation of China (61671256 and 62071259 to L.C., 31760247 to H.Z. and 61662055 to Y.X.). Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (NJYT-20-B05 to Y.X.), and Inner Mongolia University of Science and Technology Innovation Fund for Excellent Young Scholars (2019YQL01 to Y.X.).Natural Science Foundation of Inner Mongolia (2019MS03081 to J.L.)

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Authors and Affiliations

  1. College of Science, Inner Mongolia Agricultural University, Hohhot, 010018, People’s Republic of China

    Jun Li & Zuwei Yan

  2. School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, 014010, People’s Republic of China

    Jun Li, Hongyu Zhao, Yongqiang Xing, Tongling Zhao & Lu Cai

  3. Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, Inner Mongolia University of Science and Technology, Baotou, 014010, People’s Republic of China

    Jun Li, Hongyu Zhao, Yongqiang Xing, Tongling Zhao & Lu Cai

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  1. Jun Li
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  2. Hongyu Zhao
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  3. Yongqiang Xing
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  4. Tongling Zhao
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  5. Lu Cai
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Contributions

L Cai, ZW Yan planed the experiments and supplied the resources. J Li, TL Zhao has carried out the experiments, obtained the data and wrote the manuscript. HY Zhao, YQ Xing has helped the author with their valuable suggestions in the research work and writing the article.

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Correspondence to Lu Cai or Zuwei Yan.

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Li, J., Zhao, H., Xing, Y. et al. A Genome-Wide Analysis of the Gene Expression and Alternative Splicing Events in a Whole-Body Hypoxic Preconditioning Mouse Model. Neurochem Res 46, 1101–1111 (2021). https://doi.org/10.1007/s11064-021-03241-0

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