Multi-time points RNA-seq screening identifies key transcription factors and splicing factors responsive to intermittent hypoxia in the mouse hippocampus.

Abstract

Intermittent hypoxia (IH) is a hallmark pathological feature of obstructive sleep apnea and a critical risk factor for neurodegenerative diseases such as Alzheimer's disease. Transcription factors (TFs) and splicing factors (SFs) serve as pivotal regulators orchestrating cellular adaptations to hypoxia. This study aimed to elucidate the dynamic changes and identify candidate key TFs and SFs in the mouse hippocampus under IH. By establishing an IH mouse model (7% O, 1/3/5/7 weeks) and integrating multi-time points RNA-seq with bioinformatic analysis and experimental validation, we systematically identified putative core TFs and SFs involved in hippocampal hypoxia response and inferred their potential functions. Our study revealed that the TFs Lef1 and Foxj1, along with the SF Rbm47, emerge as candidate key regulators. Lef1 may modulate apoptosis-related genes such as Il31ra, while Foxj1 could be linked to ciliary function and neural development by regulating genes like Rsph1. The SF Rbm47 potentially contributes to hippocampal hypoxic adaptation by modulating alternative splicing of genes such as Apc and Hnrnpa2b1. The Lef1 gene itself undergoes alterations in exon retention rates during intermittent hypoxia. These findings provide critical data to decipher hippocampal IH adaptation and offer theoretical insights into the mechanisms of AD and related neurodegenerative disorders.