Diurnal control of iron responsive element (IRE)-containing mRNAs through iron regular proteins IRP1 and IRP2 is mediated by feeding rhythms

An important mechanism for the maintenance of cellular iron homeostasis involves iron regulatory proteins (IRP1/2) interacting with mRNAs containing iron-responsive elements (IREs). IRPs act as sensors of metabolic cues, foremost of iron itself. Under high iron concentrations, IRPs inhibit the translation or increase the stability, respectively, of mRNAs with 5 or 3 UTR-located IREs. Historically among the first examples of translational regulation of a mammalian mRNA altogether, and of considerable clinical importance, translational control of Ferritin expression has been extensively studied, revealing dominant hepatic regulation through IRP2. Here, we investigate regulation of Ferritin and other IRE-containing transcripts as a function of time-of-day in mouse liver. We uncover high-amplitude diurnal rhythms affecting the translation and stability of several IRE-containing mRNAs that is in line with maximal IRP activity at the onset of the dark phase of the day a timepoint likely not sampled in previous studies on IRP/IRE regulation. Ribosome profiling of livers deficient for either of the two IRPs reveals that IRP2 mediates regulation of IRE-containing transcripts in the light phase, but translational repression at dark onset ensues even in IRP2-deficient livers, conceivably due to IRP1 activity that can complement IRP2 absence specifically at this time-of-day. Further analyses suggest that the rhythmicity in hepatic IRE regulation is engendered through feeding rhythms, rather than the direct activity of the liver clock. Altogether, our study hints at a novel level of regulatory complexity in a pathway that has been considered well-understood since a long time. Twenty four biological samples were used (2 genetic lines x 2 genotypes x 2 time points x 3 replicates). Briefly mice were entraiend for minimum 8 days to light:dark 12:12 (hours) under ad libitum conditions and were euthanized at Zeitgeber times ZT 5 (5 hours after lights on) and ZT12 (lights off). Three replicates per time point.