Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

Guenthner, Casey J.; Bickar, David; Harrington, Mary E.

doi:10.1016/j.neuroscience.2009.08.022

Cited by 20 publications

(16 citation statements)

References 56 publications

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“…A lack of impact of LPS treatment on PER2::LUC SCN rhythms has previously been reported by Guenthner et al . (), and indicates that activation of NF‐κB signalling via this mechanism does not impact on core clock processes. Further, in phase‐resetting experiment with 100 μg LPS at CT15, we did not observe changes in PER1 after 4 h, although there may be subsequent modulation that would be revealed at different time‐points.…”

Section: Discussionmentioning

confidence: 98%

NF‐κB signalling is involved in immune‐modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock

O'Keeffe

Beynon

Davies

et al. 2017

Eur J of Neuroscience

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Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.

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Section: Discussionmentioning

confidence: 98%

NF‐κB signalling is involved in immune‐modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock

O'Keeffe

Beynon

Davies

et al. 2017

Eur J of Neuroscience

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“…Perhaps, such subjects have subtle defects in the hypothalamic-pituitary-adrenal axis, as has been described in severely symptomatic, biochemically active subjects with AIP (46). Or, perhaps, these more subtle changes are due to mild relative heme deficiencies, leading to defects in clock-controlled genes and circadian rhythms (24, 43, 45, 47). …”

Section: Discussionmentioning

confidence: 99%

“…In this study, subjects with depression that was more than mild, as assessed by the Beck Depression Inventory, were excluded. Because of recent evidence linking haem to clock-controlled proteins and circadian rhythms [45], we hypothesized that subjects with biochemically active acute porphyria would prove to have abnormalities in their circadian rhythms. Although our results did not reveal major disturbances, they did show decreases in levels of total serum cortisol in AIP subjects with biochemical activity and, especially, a blunting of the normal circadian increase in these levels that normally occurs in the early morning ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Circadian rhythms in acute intermittent porphyria – a pilot study

Larion

Caballes

Hwang

et al. 2013

Eur J Clin Investigation

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Acute intermittent porphyria (AIP) is an inherited disorder of heme synthesis wherein a partial deficiency of porphobilinogen [PBG] deaminase [PBGD], with other factors may give rise to biochemical and clinical manifestations of disease. The biochemical hallmarks of active AIP are relative hepatic heme deficiency and uncontrolled up-regulation of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1] with overproduction of ALA and PBG. The treatment of choice is intravenous heme, which restores the deficient regulatory heme pool of the liver and represses ALAS1. Recently, heme has been shown to influence circadian rhythms by controlling their negative feedback loops. We evaluated whether subjects with AIP exhibited an altered circadian profile. Over a 21 h period, we measured levels of serum cortisol, melatonin, ALA, PBG, and mRNA levels [in peripheral blood mononuclear cells] of selected clock-controlled genes and genes involved in heme synthesis in 10 Caucasian [European-American] women who were either post-menopausal or had been receiving female hormone therapy, 6 of whom have AIP and 4 do not and are considered controls. Four AIP subjects with biochemical activity exhibited higher levels of PBG and lower levels and dampened oscillation of serum cortisol, and a trend for lower levels of serum melatonin, than controls or AIP subjects without biochemical activity. Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 am and 11 pm, whereas mRNA levels of ALAS1, ALAS2, and PBGD were increased only at 11 pm in subjects with active AIP. This pilot study provides evidence for disturbances of circadian markers in women with active AIP that may trigger or sustain some common clinical features of AIP.

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“…The binding of heme to the HRM of Period 2 (Per2) enhances its proteasomal degradation in immortalized cells (97). Heme also has been shown to dampen Per2 rhythm in mouse suprachiasmatic nucleus explants (98). Per forms a heterodimeric complex with Cry that inhibits the transcriptional activator function of Bmal1-CLOCK, whereas Rev-erb NRs feed back, repressing the transcription of Bmal1 and CLOCK, which also has been shown to bind heme (99), although this binding is claimed to be nonspecific (100).…”

Section: An Unknown Factor Present In Cell Extracts Mediates the Effementioning

confidence: 99%

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

Carter

Gupta

Ragsdale

2016

Journal of Biological Chemistry

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Rev-erb␣ and Rev-erb␤ are heme-binding nuclear receptors (NR) that repress the transcription of genes involved in regulating metabolism, inflammation, and the circadian clock. Previous gene expression and co-immunoprecipitation studies led to a model in which heme binding to Rev-erb␣ recruits nuclear receptor corepressor 1 (NCoR1) into an active repressor complex. However, in contradiction, biochemical and crystallographic studies have shown that heme decreases the affinity of the ligand-binding domain of Rev-erb NRs for NCoR1 peptides. One explanation for this discrepancy is that the ligand-binding domain and NCoR1 peptides used for in vitro studies cannot replicate the key features of the full-length proteins used in cellular studies. However, the combined in vitro and cellular results described here demonstrate that heme does not directly promote interactions between full-length Rev-erb␤ (FLRev-erb␤) and an NCoR1 construct encompassing all three NR interaction domains. NCoR1 tightly binds both apo-and heme-replete FLRev-erb␤⅐DNA complexes; furthermore, heme, at high concentrations, destabilizes the FLRev-erb␤⅐NCoR1 complex. The interaction between FLRev-erb␤ and NCoR1 as well as Reverb␤ repression at the Bmal1 promoter appear to be modulated by another cellular factor(s), at least one of which is related to the ubiquitin-proteasome pathway. Our studies suggest that heme is involved in regulating the degradation of Rev-erb␤ in a manner consistent with its role in circadian rhythm maintenance. Finally, the very slow rate constant (10 ؊6 s ؊1 ) of heme dissociation from Rev-erb␤ rules out a prior proposal that Reverb␤ acts as an intracellular heme sensor.Nuclear receptors (NRs) 2 are eukaryotic transcription factors that activate or repress gene expression in response to binding small signaling molecules such as steroid hormones, lipophilic vitamins, and fatty acids (1). Genes regulated by NRs are involved in a myriad of cellular processes ranging from metabolic homeostasis to growth and development. The subjects of this article, Rev-erb␣ and Rev-erb␤, are NRs that have overlapping functions and tissue expression patterns (2-9) and are under circadian control (10 -12). Rev-erb NRs repress the transcription of key genes, e.g. Bmal1, CLOCK, and Rev-erb␣ itself, involved in regulating the molecular clock (13)(14)(15). This is accomplished in part through the formation of a heterodimeric Bmal1-CLOCK complex that activates the transcription of clock-controlled genes including Rev-erb␣/␤, completing a critical feedback loop required for circadian rhythm maintenance (6, 7). Rev-erb␣ and Rev-erb␤ also regulate the expression of genes involved in gluconeogenesis, lipid homeostasis, and immune responses, ultimately synchronizing these processes to the diurnal cycle (16 -21).The multiple functions of NRs (DNA, ligand, and coregulator binding) are accomplished through their modular structure (22, 23). The N-terminal A/B domain is hypervariable, is involved in ligand-independent transcriptional regulation, and is subject to ...

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Heme reversibly damps PERIOD2 rhythms in mouse suprachiasmatic nucleus explants

Cited by 20 publications

References 56 publications

NF‐κB signalling is involved in immune‐modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock

NF‐κB signalling is involved in immune‐modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock

Circadian rhythms in acute intermittent porphyria – a pilot study

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

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