De novo annotation of lncRNA HOTAIR transcripts by long-read RNA capture-seq reveals a differentiation-driven isoform switch.

Background: LncRNAs are tissue-specific and emerge as important regulators of various biological processes and as disease biomarkers. HOTAIR is a well-established pro-oncogenic lncRNA which has been attributed a variety of functions in cancer and native contexts. However, a lack of an exhaustive, cell type-specific annotation questions whether HOTAIR functions are supported by the expression of multiple isoforms.

Results: Using a capture long-read sequencing approach, we characterize HOTAIR isoforms expressed in human primary adipose stem cells. We find HOTAIR isoforms population displays varied splicing patterns, frequently leading to the exclusion or truncation of canonical LSD1 and PRC2 binding domains. We identify a highly cell type-specific HOTAIR isoform pool regulated by distinct promoter usage, and uncover a shift in the HOTAIR TSS usage that modulates the balance of HOTAIR isoforms at differentiation onset.

Conclusion: Our results highlight the complexity and cell type-specificity of HOTAIR isoforms and open perspectives on functional implications of these variants and their balance to key cellular processes.