A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a key transcriptional coactivator in peripheral tissues.
• Its function and brain-specific isoforms, including fusion transcripts (FTs) with repetitive elements, are poorly understood.
• Two FTs of PGC1α initiate upstream of the reference promoter, with one incorporating a SINE element.

Purpose of the Study:

• To investigate the function of brain-specific PGC1α isoforms, particularly the SINE-containing fusion transcript (FT).
• To determine the role of the SINE FT in neuronal physiology and behavior.
• To explore the impact of SINE FT mutation on gene expression in the brain.

Main Methods:

• Analysis of publicly available genomics data to identify predominant PGC1α isoforms in neurons.
• Generation and behavioral analysis of mice with a mutated SINE element in the PGC1α gene.
• Differential gene expression analysis in the cerebellum of mutant and wild-type mice, stratified by sex.

Main Results:

• The SINE-containing FT was identified as the predominant PGC1α isoform in neurons.
• Mutation of the SINE element in mice resulted in altered behavioral phenotypes.
• Significant upregulation of neurotransmission-related genes was observed in the female cerebellum, but not the male cerebellum, of mutant mice.

Conclusions:

• The SINE FT of PGC1α plays a significant role in neuronal physiology and behavior, with sex-specific effects on gene expression.
• These findings suggest novel functions for PGC1α isoforms in the brain, extending beyond classical mitochondrial and antioxidant roles.
• Further research is warranted before considering therapeutic modulation of PGC1α levels in neurological disorders.