Functional and mechanistic studies of human-specific long noncoding RNAs using a humanized mouse model

National Heart, Lung, And Blood Institute

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Abstract

We previously addressed the challenge of incomplete human liver lncRNA annotation by combining an isogenic humanized mouse model with Nanopore direct RNA sequencing. This approach enabled us to generate a de novo transcript-level annotation of human liver lncRNAs under diverse metabolic conditions, uncovering numerous novel transcripts and revealing many that are dynamically regulated by physiologically relevant stimuli. This resource established a foundation for investigating human liver lncRNAs in metabolic regulation. Building on this annotation, we developed a cross-species pipeline to identify functionally conserved lncRNA metabolic regulators (fcLMRs). Using the humanized liver model exposed to multiple feeding states and transcription factor activations, we identified syntenic human-mouse lncRNA pairs with conserved regulation under metabolic challenges. Correlation analyses of lncRNA–mRNA expression in humanized mice, followed by pathway enrichment, yielded 59 high-confidence fcLMRs associated with conserved metabolic pathways. These findings provide a powerful framework for prioritizing human lncRNAs with functional roles in metabolism and highlight candidates for future mechanistic studies.