RNA-independent cis-autoregulatory circuits within bidirectional gene pairs control metabolism

Many genes share promoters with another gene on the opposite DNA strand, forming bidirectional pairs. During metabolic transitions, most pairs are coordinately regulated in the liver, in part through chromatin topology. In pairs composed of a long noncoding RNA (lncRNA) and a protein-coding gene (PCG), lncRNA transcription cis-activates PCG transcription by establishing an active chromatin environment at the promoter-proximal enhancer of PCG. Reciprocally, PCG transcription cis-inhibits lncRNA transcription, forming internal cis-autoregulatory circuits. Both directions of regulation are independent of the RNA products but dependent on the transcription process itself. Similar promoter-proximal enhancer signatures and cis-autoregulatory circuits are present in many lncRNA/PCG and PCG/PCG pairs, underscoring the generalizability of these circuits. Using the conserved lncRNA/PCG pair Gm15663/Tmtc2 as a model, we show that blocking lncRNA transcription in the liver in vivo disrupts this coordinated regulation, decreasing Tmtc2 expression and inducing hepatic steatosis. These data demonstrate the physiological importance of transcription-dependent cis-autoregulatory circuits in metabolic homeostasis and their potential for dysregulation in disease.