Traumatic brain injury increased IGF-1B mRNA and altered IGF-1 exon 5 and promoter region epigenetic characteristics in the rat pup hippocampus.

Abstract

Traumatic brain injury (TBI) is a major cause of acquired cognitive disability in childhood. Such disability may be blunted by enhancing the brain's endogenous neuroprotective response. An important endogenous neuroprotective response is the insulin-like growth factor-1 (IGF-1) mRNA variant, IGF-1B. IGF-1B mRNA, characterized by exon 5 inclusion, encodes the IGF-1 and Eb peptides. IGF-1A mRNA excludes exon 5 and encodes the IGF-1 and Ea peptides. A region in the human IGF-1B homologue acts as an exon-splicing enhancer (ESE) to increase IGF-1B mRNA. It is not known if TBI is associated with increased brain IGF-1B mRNA. Epigenetic modifications may underlie altered gene expression in the brain after TBI. We hypothesized that TBI would increase hippocampal IGF-1B mRNA in 17-day-old rats, associated with DNA methylation and/or histone modifications at the promoter site 1 (P1) or exon 5/ESE region. Hippocampi from rat pups after controlled cortical impact (CCI) were used to measure IGF-1B mRNA, DNA methylation, and histone modifications at the P1, P2, and exon5/ESE regions. In CCI hippocampi, IGF-1B mRNA peaked at post-injury day (PID) 2 (1700±320% sham), but normalized by PID 14. IGF-1A peaked at PID 3 (280±52% sham), and remained elevated at PID 14. Increased IGF-1B mRNA was associated with increased methylation at P1, and increased histone modifications associated with gene activation at P2 and exon5/ESE, together with differential methylation in the exon 5/ESE regions. We report for the first time that hippocampal IGF-1B mRNA increased after developmental TBI. We speculate that epigenetic modifications at the P2 and exon 5/ESE regions are important in the regulation of IGF-1B mRNA expression. The exon 5/ESE region may present a means for future therapies to target IGF-1B transcription after TBI.

• Authors: Michelle E Schober, Xingrao Ke, Bohan Xing, Benjamin P Block, Daniela F Requena, Robert McKnight, Robert H Lane
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 29 Issue 11 Pg. 2075-85 (Jul 20 2012) ISSN: 1557-9042 [Electronic] United States
• PMID: 22413999 (Publication Type: Journal Article)

Chemical References

• RNA, Messenger
• Insulin-Like Growth Factor I

Topics

• Animals
• Brain Injuries (genetics, metabolism)
• Chromatin Immunoprecipitation
• Disease Models, Animal
• Epigenesis, Genetic (genetics)
• Exons (genetics)
• Hippocampus (metabolism)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Male
• Promoter Regions, Genetic
• RNA, Messenger (analysis, genetics)
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction