The Long Noncoding RNA Ctcflos Orchestrates Transcriptional and Post-Transcriptional Alternative Splicing Programs Essential for Thermogenic Gene Expression in Brite Adipocytes

The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing great interest in understanding the intricate regulatory mechanisms underlying this process. Brite adipogenesis demands complex spatial and temporal orchestration of multiple regulatory factors. The underlying molecular network, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) are emerging as a versatile class of modulators able to control many steps within the differentiation machinery including chromatin accessibility, gene transcription, splicing and translation. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we here identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a bi-functional regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos regulated gene transcription and splicing of the key browning factor Prdm16: Ctcflos controls its general expression levels as well as a shift towards the isoform that is specific for the thermogenic gene program. Beyond Prdm16, our transcriptome wide search for splice variants identified Ctcflos-dependent alternative splicing of multiple further factors that together might boost brite adipogenesis. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.