Chronic intestinal pseudo-obstruction (CIPO) is a rare but life-threatening disorder characterized by severe gastrointestinal (GI) dysmotility. Mutations that impair the expression or function of proteins involved in the smooth muscle cell (SMC) contractile apparatus are the most common cause of myopathic CIPO. Long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides with no apparent protein-coding potential, outnumber protein-coding genes and have been shown to play critical roles in various physiological and pathological processes.
Using a data mining approach to interrogate multiple independent omics datasets, we identified a novel lncRNA, cardiac mesoderm enhancer-associated non-coding RNA (CARMN), as the most abundantly expressed lncRNA in visceral SMCs in both humans and mice. Unexpectedly, both germline and SMC-specific inducible deletion of Carmn in mice led to premature lethality due to GI pseudo-obstruction, driven by downregulation of numerous smooth muscle contractile genes, including the known CIPO-associated gene MYLK. Mechanistically, CARMN promotes the smooth muscle contractile gene program by activating the essential transcriptional complex SRF/MYOCD through direct interaction with MYOCD.
These findings establish CARMN as indispensable for GI function and identify it as the first lncRNA with a critical role in regulating GI motility. Loss of Carmn expression, whether through global deletion during development or SMC-specific inducible ablation in adulthood caused a severe GI motility disorder characterized by lethal visceral myopathy, resembling SMC dysfunction-mediated CIPO in humans. This study raises the possibility that polymorphisms or mutations in the CARMN gene that impair its expression, or function may underlie certain cases of idiopathic CIPO.

Long non-coding RNAs; RNA coding potential; Feature Enhancement; Ensemble Method