Brief naturalistic stress induces an alternative splice variant of SMG-1 lacking exon 63 in peripheral leukocytes.
Alternative splicing (AS) not only regulates the gene expression program in response to surrounding environment, but also produces protein isoforms with unique properties under stressful conditions. However, acute psychological stress-initiated AS events have not been documented in human studies. After assessments of changes in salivary cortisol levels and anxiety among 28 fourth-grade medical students 7 weeks prior to, 1 day before, immediately after, and 1 week after an examination for promotion, we selected 5 male students, who showed a typical stress response, and screened AS events in their circulating leukocytes using the GeneChip human exon 1.0 ST array. AS events of 27 genes with splicing indices >1.0 could be detected between immediately after and either 7 weeks before, 1 day before, or 1 week after the examination. The examination stress preferentially caused skipping rather than inclusion: 21 out of the 27 pre-mRNAs underwent skipping of exons, and skipping in 3'UTR was observed in 8 genes. Among the candidate genes, real-time reverse transcription PCR validated the stress-initiated skipping of exon 63 of SMG-1 that encodes a phosphatidylinositol 3-kinase-related protein kinase crucial for activations of p53-dependent pathways and nonsense-mediated mRNA decay. Our results indicate a significant impact of brief naturalistic stressors on AS-mediated regulation of gene expression in peripheral leukocytes, and suggest the SMG-1 splice variant as a potential biomarker for acute psychological stress.
Kurokawa
Ken
K
Department of Stress Science, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Kuwano
Yuki
Y
Tominaga
Kumiko
K
Kawai
Tomoko
T
Katsuura
Sakurako
S
Yamagishi
Naoko
N
Satake
Yuzuru
Y
Kajita
Keisuke
K
Tanahashi
Toshihito
T
Rokutan
Kazuhito
K
D017398:Alternative Splicing / Q000502:physiology*; D000704:Analysis of Variance; D005091:Exons / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011569:Psychiatric Status Rating Scales; D027544:Salvia / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult
D006854:Hydrocortisone; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C514704:SMG1 protein, human