title: 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.affiliation: Division of Critical Care, Department of Pediatrics, University of Utah School of Medicine Salt Lake City, Utah 84158, USA. michelle.schober@hsc.utah.edu
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Schober
authors.forename: Xingrao
authors.initials: X
authors.lastname: Ke
authors.forename: Bohan
authors.initials: B
authors.lastname: Xing
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Block
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Requena
authors.forename: Robert
authors.initials: R
authors.lastname: McKnight
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lane
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I