More Complex Than Expected: Control of IRE mRNAs

The Gatfield and Galy labs investigated the rhytmic regulation of iron homeostasis through the control of iron responsive element (IRE) containing mRNAs. These were thought to be regulated in the liver mainly by iron regulatory protein 2 (IRP2) and not iron regulatory protein 1 (IRP1). They found large diurnal oscillations of IRE contianing mRNAs even in the absence of IRP2 and these diurnal oscillations persist in the absence of the circadian clock when a feeding rhytm is maintained. These findings reveal a further dynamic and regulatory complexity of a metabolic pathway which was thought to be understood. The paper "Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms" has been published in Genome Biology.

Background: Cellular iron homeostasis is regulated by iron regulatory proteins (IRP1 and IRP2) that sense iron levels (and other metabolic cues) and modulate mRNA translation or stability via interaction with iron regulatory elements (IREs). IRP2 is viewed as the primary regulator in the liver, yet our previous datasets showing diurnal rhythms for certain IRE-containing mRNAs suggest a nuanced temporal control mechanism. The purpose of this study is to gain insights into the daily regulatory dynamics across IRE-bearing mRNAs, specific IRP involvement, and underlying systemic and cellular rhythmicity cues in mouse liver.
Results: We uncover high-amplitude diurnal oscillations in the regulation of key IRE-containing transcripts in the liver, compatible with maximal IRP activity at the onset of the dark phase. Although IRP2 protein levels also exhibit some diurnal variations and peak at the light-dark transition, ribosome profiling in IRP2-deficient mice reveals that maximal repression of target mRNAs at this timepoint still occurs. We further find that diurnal regulation of IRE-containing mRNAs can continue in the absence of a functional circadian clock as long as feeding is rhythmic.
Conclusions: Our findings suggest temporally controlled redundancy in IRP activities, with IRP2 mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. Moreover, we highlight the significance of feeding-associated signals in driving rhythmicity. Our work highlights the dynamic nature and regulatory complexity in a metabolic pathway that had previously been considered well-understood.

Read the Publication in Genome Biology (Open Access)

Website Gatfield Lab

Abstract, figure and title from Nadimpalli, Katsioudi, Arpa et al. (2024) Genome Biology published under a CC BY 4.0 license.