Metabolic and circadian inputs encode anticipatory biogenesis of hepatic fed microRNAs.

Starvation and refeeding are mostly unanticipated in the wild in terms of duration, frequency, and nutritional value of the refed state. Notwithstanding this, organisms mount efficient and reproducible responses to restore metabolic homeostasis. Hence, it is intuitive to invoke expectant molecular mechanisms that build anticipatory responses to enable physiological toggling during fed-fast cycles. In this regard, we report anticipatory biogenesis of oscillatory hepatic microRNAs that peak during a fed state and inhibit starvation-responsive genes. Our results clearly demonstrate that the levels of primary and precursor microRNA transcripts increase during a fasting state, in anticipation of a fed response. We delineate the importance of both metabolic and circadian cues in orchestrating hepatic fed microRNA homeostasis in a physiological setting. Besides illustrating metabo-endocrine control, our findings provide a mechanistic basis for the overarching influence of starvation on anticipatory biogenesis. Importantly, by using pharmacological agents that are widely used in clinics, we point out the high potential of interventions to restore homeostasis of hepatic microRNAs, whose deregulated expression is otherwise well established to cause metabolic diseases.

Metabolic regulation of CTCF expression and chromatin association dictates starvation response in mice and flies.

Coordinated temporal control of gene expression is essential for physiological homeostasis, especially during metabolic transitions. However, the interplay between chromatin architectural proteins and metabolism in regulating transcription is less understood. Here, we demonstrate a conserved bidirectional interplay between CTCF (CCCTC-binding factor) expression/function and metabolic inputs during feed-fast cycles. Our results indicate that its loci-specific functional diversity is associated with physiological plasticity in mouse hepatocytes. CTCF differential expression and long non-coding RNA-Jpx mediated changes in chromatin occupancy, unraveled its paradoxical yet tuneable functions, which are governed by metabolic inputs. We illustrate the key role of CTCF in controlling temporal cascade of transcriptional response, with effects on hepatic mitochondrial energetics and lipidome. Underscoring the evolutionary conservation of CTCF-dependent metabolic homeostasis, CTCF knockdown in flies abrogated starvation resistance. In summary, we demonstrate the interplay between CTCF and metabolic inputs that highlights the coupled plasticity of physiological responses and chromatin function.