Identification of region-specific gene isoforms in the human brain using long-read transcriptome sequencing

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Neurological and neuropsychiatric diseases affect distinct brain regions.
• Gene expression differences across brain regions may underlie disease mechanisms.
• Limited research has precisely explored gene expression in specific human brain regions.

Purpose of the Study:

• To perform long-read RNA sequencing on multiple human brain regions.
• To identify novel gene isoforms and their regional expression patterns.
• To investigate the role of DNA methylation in isoform regulation.

Main Methods:

• Long-read RNA sequencing was performed on the cerebellum, hypothalamus, and temporal cortex from the same individuals.
• Stringent filtering criteria were applied to exclude artifactual isoforms.
• Analysis focused on genes with differential major isoforms across brain regions.

Main Results:

• Over half of the expressed isoforms were unregistered in the GENCODE reference database.
• Many genes, including GAS7, exhibited distinct major isoforms in different brain regions, even with similar overall expression levels.
• DNA methylation was identified as a potential driver of differential isoform expression.

Conclusions:

• The study highlights the importance of analyzing isoforms in disease-relevant brain sites.
• Novel, unregistered isoforms may have significant roles in regional neuronal development.
• Isoform diversity and regulation are critical aspects of brain function and disease.