LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles

Area of Science:

• Molecular Biology
• Cancer Biology
• Gene Regulation

Background:

• Alternative splicing (AS) is vital for cellular processes, and its dysregulation contributes to cancer.
• Hypoxia, prevalent in tumors, induces AS in numerous genes, but the underlying mechanisms are poorly understood.

Purpose of the Study:

• To elucidate the mechanisms governing hypoxia-induced alternative splicing.
• To investigate the role of the lncRNA MALAT1 in hypoxia-responsive AS.

Main Methods:

• Analysis of hypoxia-responsive spliced exons and their genomic locations.
• Investigating the association of MALAT1 with hypoxia-responsive genes.
• Assessing MALAT1's effect on SRSF1-pre-mRNA interactions and SRSF1 condensation.
• Evaluating the role of RNAPII in recruiting splicing factors.

Main Results:

• Hypoxia-induced spliced exons are inefficiently spliced and located near nuclear speckles.
• The speckle-enriched lncRNA MALAT1 is upregulated by hypoxia and associates with target genes.
• MALAT1 promotes AS by enhancing SRSF1 condensation, facilitating RNAPII-mediated recruitment of splicing factors to pre-mRNAs.

Conclusions:

• MALAT1 plays a critical role in orchestrating hypoxia-induced alternative splicing.
• MALAT1 organizes splicing factor condensates near nuclear speckles, enhancing splicing efficiency during hypoxia.
• This mechanism highlights a novel regulatory pathway for gene expression in the tumor microenvironment.