Integrative Omics Analysis Reveals the Regulation of Hypoxia Tolerance in Large Yellow Croaker ( <i>Larimichthys crocea</i> ) via the Lipoic Acid Synthase ( <i>lias</i> ) Gene

Hypoxia stress seriously affects the survival of aquatic animals. However, little is known about the regulation mechanism under hypoxia stress; hence, it is important to fully clarify this regulation to improve the hypoxia tolerance of aquatic animals. In this study, we integrated multi-omics data from Larimichthys crocea under hypoxic stress and validated the functions of candidate genes using multiple techniques. Genome-wide association study and transcriptome analysis identified lipoic acid synthase (lias) as an important candidate gene for hypoxia tolerance. Specifically, SNP in the second intron region of lias significantly altered the transcription levels between major haplotypes. Methylation and CUT&Tag sequencing confirmed that this significant SNP could alter the enhancer activity of lias by affecting the methylation level, and eventually affecting lias expression. Functional characterization revealed that lias can inhibit the production of α-ketoglutaric acid under hypoxia, and then negatively regulate the protein level of hypoxia-inducible factor (HIF)-1α through prolyl hydroxylase domain, resulting in less hydroxylation dependent degradation of HIF-1⍺ and more downstream target gene expression of Hap2, leading to better adaptation to the hypoxia environment. Our study provides a new research perspective for the theory of fish hypoxia tolerance.