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

ABSTRACT: Temporal and coordinated control of gene expression is vital to mount appropriate physiological responses, especially in the context of dynamic metabolic transitions. Despite this, the interplay between chromatin architectural proteins and metabolism in regulating transcription is largely unknown. Here, we demonstrate that CTCF, the transcriptional regulator and boundary insulating protein, is itself regulated by metabolic inputs and its expression is associated with fed/fasted states. Although CTCF is well established as a key determinant of gene expression programs, our results indicate that its loci-specific functional diversity is associated with physiological plasticity during fed-fast cycles. Intriguingly, CTCF ChIP-seq and its differential expression point towards a paradoxical and yet tuneable binding to chromatin, as a function of hepatic metabolic status. Given emerging literature that indicates loci-/affinity-dependent functions of CTCF, we illustrate a physiological setting for such disparate association that is possibly mediated by the abundance of a non-coding RNA, Jpx. Further, meta-analyses of fed-fast dependent global transcriptional response and CTCF occupancy hint at the crucial role of CTCF in dictating hepatic gene expression and metabolism. Importantly, altering CTCF expression influenced the temporal cascade of metabolic gene expression. Heterologous perturbation of CTCF, to levels that mimic physiological oscillation, impacted mitochondrial energetics and lipidome profiles in hepatocytes. In addition to demonstrating the significance of CTCF expression and its differential chromatin association, our study also highlights the interplay between metabolism and chromatin organizers.

ORGANISM(S): Mus musculus

PROVIDER: GSE207692 | GEO | 2023/07/04

REPOSITORIES: GEO