Iron accumulation with age alters metabolic pattern and circadian clock gene expression through the reduction of AMP-modulated histone methylation

Liu, Junhao; Zhao, Yang; Ding, Zhao; Zhao, Yue; Chen, Tingting; Ge, Weifeng; Zhang, Jianfa

doi:10.1016/j.jbc.2022.101968

Cited by 7 publications

(13 citation statements)

References 99 publications

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“…Heme can also function as a cofactor of clock genes and thus regulate biological cycles 52,53 . In addition, iron accumulation can also affect the expression of core clock genes, including PER1 and PER2, through histone methylation 18 . In the present study, we found that changes in brain iron status can influence the expression of PER1, CLOCK, and BMAL1 in various brain regions of 10‐month‐old mice.…”

Section: Discussionsupporting

confidence: 56%

“…52,53 In addition, iron accumulation can also affect the expression of core clock genes, including PER1 and PER2, through histone methylation. 18 In the present study, we found that changes in brain iron status can influence the expression of PER1, CLOCK, and BMAL1 in various brain regions of 10-month-old mice. Together, our results suggest that iron accumulation may drive disturbances in circadian and locomotor activity rhythms.…”

Section: Con Clus Ionsupporting

confidence: 55%

“…Several previous studies revealed that peripheral iron accumulation plays a key role in aging‐related shifts of circadian function; sleep disturbances have been frequently seen in iron overload‐related diseases 47,48 . On the other hand, iron supplementation in young mice (4‐week‐old) yields indistinguishable or altered expression of Per1 and Per2 in the liver 18 . Some additional studies have aimed to connect iron metabolism and circadian rhythms.…”

Section: Discussionmentioning

confidence: 99%

“…Liu et al reported that iron accumulation with age altered the metabolic pattern and expression of circadian clock genes through decreased histone methylation in the mouse liver. 18 Additionally, iron-induced redox toxicity may also lead to a disturbance in the biological circadian clock. A recent review by T. Ishii et al discusses how circadian rhythm-induced improvements in the expression of an important antioxidant pathway, brain-derived neurotrophic factor (BDNF)-Nrf2 in astrocytes, can strengthen astrocyte-neuron interactions and protect dopaminergic neurons from iron-mediated cell death (ferroptosis) and redox toxicity in rodent brains.…”

Section: Introductionmentioning

confidence: 99%

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Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

Wu,

Ren,

Wang

et al. 2024

CNS Neurosci Ther

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AimsDisturbances in the circadian rhythm are positively correlated with the processes of aging and related neurodegenerative diseases, which are also associated with brain iron accumulation. However, the role of brain iron in regulating the biological rhythm is poorly understood. In this study, we investigated the impact of brain iron levels on the spontaneous locomotor activity of mice with altered brain iron levels and further explored the potential mechanisms governing these effects in vitro.ResultsOur results revealed that conditional knockout of ferroportin 1 (Fpn1) in cerebral microvascular endothelial cells led to brain iron deficiency, subsequently resulting in enhanced locomotor activity and increased expression of clock genes, including the circadian locomotor output cycles kaput protein (Clock) and brain and muscle ARNT‐like 1 (Bmal1). Concomitantly, the levels of period circadian regulator 1 (PER1), which functions as a transcriptional repressor in regulating biological rhythm, were decreased. Conversely, the elevated brain iron levels in APP/PS1 mice inhibited autonomous rhythmic activity. Additionally, our findings demonstrate a significant decrease in serum melatonin levels in Fpn1cdh5 ‐CKO mice compared with the Fpn1flox/flox group. In contrast, APP/PS1 mice with brain iron deposition exhibited higher serum melatonin levels than the WT group. Furthermore, in the human glioma cell line, U251, we observed reduced PER1 expression upon iron limitation by deferoxamine (DFO; iron chelator) or endogenous overexpression of FPN1. When U251 cells were made iron‐replete by supplementation with ferric ammonium citrate (FAC) or increased iron import through transferrin receptor 1 (TfR1) overexpression, PER1 protein levels were increased. Additionally, we obtained similar results to U251 cells in mouse cerebellar astrocytes (MA‐c), where we collected cells at different time points to investigate the rhythmic expression of core clock genes and the impact of DFO or FAC treatment on PER1 protein levels.ConclusionThese findings collectively suggest that altered iron levels influence the circadian rhythm by regulating PER1 expression and thereby modulating the molecular circadian clock. In conclusion, our study identifies the regulation of brain iron levels as a potential new target for treating age‐related disruptions in the circadian rhythm.

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Section: Discussionsupporting

confidence: 56%

Section: Con Clus Ionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

Wu,

Ren,

Wang

et al. 2024

CNS Neurosci Ther

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show abstract

“…These knockout mice present with systemic alterations to iron homeostasis and phenotypic abnormalities, including in liver (reviewed in [44]); moreover, there are documented links between iron and the circadian timekeeping mechanism itself. For example, several core clock proteins contain heme [11, 45, 46] and the transcription of Per1 and Per2 has been reported as sensitive to iron accumulation through a mechanism that involves histone methylation state [47]. Therefore, we first explored whether whole-body Aco1 or Ireb2 knockout engendered phenotypes in entrained liver clock rhythms that could potentially confound the specific analysis of rhythmic IRP/IRE regulation.…”

Section: Resultsmentioning

confidence: 99%

Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

Nadimpalli,

Katsioudi,

Arpa

et al. 2023

Preprint

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A central mechanism for cellular iron homeostasis involves iron regulatory proteins, IRP1 and IRP2, that interact with iron regulatory elements (IREs) on mRNAs. IRPs act as sensors of metabolic cues (foremost of iron itself) and can regulate either translation or transcript stability, depending on IRE location within the mRNA. In liver, IRP2 is widely considered the principle player mediating IRE regulation. Here, we uncover high-amplitude diurnal rhythms in the regulation of several prominent IRE-containing mRNAs in liver, compatible with maximal IRP activity at the onset of the dark phase of the day (a timepoint likely underrepresented in previous studies on IRP/IRE regulation). We find that IRP2 protein abundance itself oscillates over the day, yet ribosome profiling in livers from IRP2-deficient mice uncovers that IRP2 is dispensable for maximal repression of its rhythmically regulated target mRNAs at the time of its highest abundance, i.e. the light-dark transition. These findings are compatible with temporally controlled redundancy in IRP activities, with IRP2 exclusively mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. We further unveil that the identified diurnal IRP/IRE regulation can ensue in the absence of a functional circadian clock as long as feeding is rhythmic, and that it follows feeding rhythms also in the presence of a clock, thus identifying feeding-associated signals as the dominant driver of IRP/IRE rhythmicity. Altogether, our study identifies a novel level of regulatory control and complexity in a metabolic pathway that had been considered well-understood since a long time.

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PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse

Ding,

Ge,

et al. 2023

Journal of Biological Chemistry

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Iron accumulation with age alters metabolic pattern and circadian clock gene expression through the reduction of AMP-modulated histone methylation

Cited by 7 publications

References 99 publications

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse

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