Platform-based gene regulation by an endoderm-specific lncRNA via stabilizing nuclear speckles

Nuclear speckles (NSs), one of the key non-membrane nuclear bodies, participate in transcription, RNA processing, and chromatin organization, yet their precise functions and mechanisms in vivo remain elusive. Here we show that Falcor, an endoderm-specific long non-coding RNA (lncRNA), is necessary and sufficient for maintaining structural integrity of NSs in mouse liver cells. Disruption and reinstatement of NSs by Falcor coordinately regulate more than one thousand genes, including those related to metabolic processes. Falcor locates in the core of NSs, and interacts with Zinc finger CCCH domain-containing protein 11A (ZC3H11A), thereby facilitating phase separation to maintain NSs' structure. Furthermore, specific knockout of Falcor in the mouse liver uncovered its pivotal role in governing metabolic homeostasis, and its absence affords protection against diet-induced liver steatosis, obesity, and metabolic disorders. Collectively, our study demonstrated essential roles of Falcor in NSs maintenance and regulating metabolic homeostasis, which imply the importance of lineage-specific lncRNAs in “platform-based” gene regulation via NSs during pathophysiological processes. To test the functions of Falcor in NSs, we knocked down its gene expression through short hairpin RNA (shRNA)-based RNA interference (RNAi) in mouse AML12 hepatocytes.To further investigate the collaboratively regulatory role of Falcor and ZC3H11A on downstream genes, we conducted RNA-seq analysis on AML12 cell lines with the conventional shRNA-based knockdown of Falcor or ZC3H11A.Next, we explored the functions of Falcor under normal physiological conditions. We further explored the effect of Falcor on metabolism under pathological conditions.