A single-nucleotide polymorphism induced alternative splicing in Tacr3 involves in hypoxic-ischemic brain damage

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Single-nucleotide polymorphisms (SNPs) and alternative splicing (AS) are implicated in diseases, but their roles in hypoxic-ischemic encephalopathy (HIE) pathogenesis in developing brains are unclear.
• The gene Tacr3 is linked to normosmic congenital hypogonadotropic hypogonadism, with its specific relationship to HIE remaining largely undetermined.

Purpose of the Study:

• To investigate differentially expressed mRNAs, associated SNPs, and AS in neonatal rats with HIE.
• To determine if AS is associated with SNPs under HIE pathological conditions.
• To explore the role of Tacr3 in HIE and its potential as a therapeutic target.

Main Methods:

• Neonatal rat model of HIE was established using Sprague-Dawley rats on postnatal day 7.
• RNA sequencing was employed to analyze SNP mRNA expression profiles in hypoxic-ischemic (HI) and sham brains.
• Bioinformatics analysis, including exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, was used to identify key genes and SNPs.

Main Results:

• Four genes (Mdfic, Lpp, Bag3, and Tacr3) associated with HIE, exhibiting SNPs and AS, were identified.
• Tacr3 was found to be specifically associated with HIE through two SNPs: 258547789 G>A (within Alt First Exon) and 258548573 G>A (outside Alt First Exon).
• The study provides evidence linking specific SNPs and AS in Tacr3 to HIE.

Conclusions:

• The study offers new insights into the role of Tacr3 in HIE pathogenesis.
• Tacr3, influenced by specific SNPs and AS, is identified as a potential therapeutic target for HIE treatment.
• Further clinical trials may explore Tacr3-based interventions for HIE.