Promoter methylation analysis of seven clock genes in Parkinson's disease

doi:10.1016/j.neulet.2011.12.007

Neuroscience Letters

Volume 507, Issue 2, 24 January 2012, Pages 147-150

https://doi.org/10.1016/j.neulet.2011.12.007 Get rights and content

Abstract

The expression of clock genes is altered in leukocytes from patients with Parkinson's disease (PD). However, the underlying mechanisms are unknown. To determine whether abnormal CpG methylation contributes to the dysregulated expression of these genes, the methylation status of the promoters of seven major human clock genes, PER1, PER2, CRY1, CRY2, Clock, NPAS2, and BMAL1, was examined using methylation-specific PCR (MSP) and sequencing in 206 PD patients and 181 healthy controls. This analysis revealed that most clock gene promoters were devoid of methylation. Methylation was only detectable in the CRY1 and NPAS2 promoters. Interestingly, the methylation frequency of the NPAS2 promoter was significantly decreased in PD patients. These results suggest that altered promoter methylation may contribute to the abnormal expression of clock genes in PD.

Highlights

► Methylation status of seven clock genes was examined in PD patients and controls. ► Most clock gene promoters were free from methylation. ► Methylation was detectable in the CRY1 and NPAS2 promoters. ► The methylation frequency of the NPAS2 promoter was significantly decreased in PD patients.

Section snippets

Acknowledgments

The authors wish to thank Jingyan Song for helpful discussion. Research support was provided by the National Natural Science Foundation of China (81071011, 30940039, 30970939), the National 973 Project Grant of China (2011CBA00408), the Program for New Century Excellent Talents in University (NCET-10-0013), and the Science foundation of Ministry of Education of China (11120066).

References (24)

Y. Baba et al.
Alterations of T-lymphocyte populations in Parkinson's disease
Parkinsonism Relat. Disord.
(2005)
A. Bredberg et al.
Cytostatic drug treatment causes seeding of gene promoter methylation
Eur. J. Cancer.
(2007)
D.J. Buysse et al.
The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research
Psychiatry Res.
(1989)
H. Ding et al.
Decreased expression of Bmal2 in patients with Parkinson's disease
Neurosci. Lett.
(2011)
R. Holliday et al.
DNA methylation and mutation
Mutat. Res.
(1993)
M.S. Hsu et al.
Uncoupling of promoter methylation and expression of Period1 in cervical cancer cells
Biochem. Biophys. Res. Commun.
(2007)
Y. Ji et al.
Methylation analyses on promoters of mPER1, mPER2, and mCRY1 during perinatal development
Biochem. Biophys. Res. Commun
(2010)
H.C. Liu et al.
A pilot study for circadian gene disturbance in dementia patients
Neurosci. Lett.
(2008)
N. Preitner et al.
The orphan nuclear receptor REV-ERB alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator
Cell
(2002)
T.K. Sato et al.
A functional genomics strategy reveals Rora as a component of the mammalian circadian clock
Neuron
(2004)

Z.X. Zhang et al.

Parkinson's disease in China: prevalence in Beijing, Xian, and Shanghai

Lancet

(2005)

J.C. Brandes et al.

Optimal primer design using the novel primer design program: MSP primer provides accurate methylation analysis of the ATM promoter ATM is not frequently methylated in cancer

Oncogene

(2007)

Cited by (61)

Molecular crosstalk between circadian clock and NLRP3 inflammasome signaling in Parkinson's disease
2024, Heliyon
Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Research has recently found that both animal models and patients with PD have circadian dysfunction, accompanied by abnormal expression of circadian genes and proteins, which implies that the circadian clock plays a crucial role in PD etiopathogenesis. In addition, a strong relationship between NLRP3 inflammasome signaling and PD has been observed. Meanwhile, the activation of the NLRP3 inflammasome is highly relevant to dysfunctions of the molecular clock. Therefore, alleviating the neuroinflammation caused by NLRP3 inflammasome signaling by adjusting the abnormal molecular clock may be a potential strategy for preventing and treating PD. In this article, we have reviewed the potential or direct relationship between abnormalities of the circadian clock and NLRP3 inflammasome signaling in PD.
Deciphering clock genes as emerging targets against aging
2022, Ageing Research Reviews
The old people often suffer from circadian rhythm disturbances, which in turn accelerate aging. Many aging-related degenerative diseases such as Alzheimer's disease, Parkinson's disease, and osteoarthritis have an inextricable connection with circadian rhythm. In light of the predominant effects of clock genes on regulating circadian rhythm, we systematically present the elaborate network of roles that clock genes play in aging in this review. First, we briefly introduce the basic background regarding clock genes. Second, we systemically summarize the roles of clock genes in aging and aging-related degenerative diseases. Third, we discuss the relationship between clock genes polymorphisms and aging. In summary, this review is intended to clarify the indispensable roles of clock genes in aging and sheds light on developing clock genes as anti-aging targets.
The effect of 3-Methyl-4-Nitrophenol on the early ovarian follicle development in mice by disrupting the clock genes expression
2022, Chemico-Biological Interactions
3-Methyl-4-Nitrophenol (PNMC) is the main degradation product of organophosphate insecticide fenitrothion and a major component of diesel exhaust particles, which is now becoming a widely spread environmental endocrine disruptor. Previous reports showed PNMC exposure can affect the female reproductive system and ovarian function; however, the mechanism remains unclear. The main purpose of this study is to clarify the mechanism underlying the adverse effects of neonatal PNMC treatment on ovarian functions. The neonatal female mice were exposed to 10 mg/kg PNMC and the ovaries were collected on the 7th day after birth. The changes of follicular composition in mice ovaries were analyzed by histological staining, which showed that the proportion of primordial follicles in the ovaries treated by PNMC decreased, while the proportion of secondary follicles increased. The ovarian function was also investigated by detecting the expressions of steroidogenic enzymes (Star, Cyp11a1, Hsd3b1, Cyp17a1, Cyp19a1), gonadotropin receptors (Fshr and Lhr), androgen receptor (Ar), and estrogen receptors (Esr1 and Esr2) by immunohistochemistry or/and real-time quantitative PCR. The expression of Hsd3b1, Cyp17a1 and Esr2 were increased significantly in the PNMC exposed ovaries. Moreover, the expression patterns of clock genes (Bmal1, Clock, Per1, Per2, Cry1, Cry2 and Nr1d1) were disrupted in the ovaries after PNMC exposure. Furthermore, either the expression of DNA Methyltransferase Dnmt3b, or the methylation ratio of CpG islands in the upstream of Cry1 promoter regions were significantly decreased in PNMC exposed ovaries. Altogether, these results indicate that PNMC exposure affects follicle development and ovarian function by interfering with the epigenetic modification and disrupting the expression of clock genes.
Roles of clock genes in the pathogenesis of Parkinson's disease
2022, Ageing Research Reviews
Citation Excerpt :
This is exemplified by Lin et al., who investigated a possible contribution of clock genes promoter methylation in PD’s pathogenesis (Lin et al., 2012). This study, which was conducted on 206 PD patients and 181 healthy controls, showed that only CRY1 and NPAS2 (the paralog of CLOCK) promoters exhibited methylation, and only the latter was significantly hypomethylated in PD patients (Lin et al., 2012). Nonetheless, other genes, including CLOCK, BMAL1, PER1, PER2 and CRY2, were found to be not regulated epigenetically by DNA methylation in both cases and controls.
Parkinson's disease (PD) is a common motor disorder that has become increasingly prevalent in the ageing population. Recent works have suggested that circadian rhythms disruption is a common event in PD patients. Clock genes regulate the circadian rhythm of biological processes in eukaryotic organisms, but their roles in PD remain unclear. Despite this, several lines of evidence point to the possibility that clock genes may have a significant impact on the development and progression of the disease. This review aims to consolidate recent understanding of the roles of clock genes in PD. We first summarized the findings of clock gene expression and epigenetic analyses in PD patients and animal models. We also discussed the potential contributory role of clock gene variants in the development of PD and/or its symptoms. We further reviewed the mechanisms by which clock genes affect mitochondrial dynamics as well as the rhythmic synthesis and secretion of endocrine hormones, the impairment of which may contribute to the development of PD. Finally, we discussed the limitations of the currently available studies, and suggested future potential studies to deepen our understanding of the roles of clock genes in PD pathogenesis.
Epigenetics and cognitive disorders
2021, Epigenetics in Psychiatry
Epigenetic marks, such as DNA methylation and histone modifications, play a fundamental role in the neuronal plasticity required for learning and memory. As a consequence, changes of the epigenetic landscape can contribute to the age-related cognitive decline as well as to cognitive impairment and neurodegeneration. This chapter describes the available knowledge of the contribution of changes in DNA methylation and histone modifications to Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease.
Studies in animal models of disease and neuronal cell cultures have shown that the environment plays a fundamental role in determining long-lasting epigenetic changes relevant to neurodegeneration, and there is increasing evidence suggesting that many of the causative genes of familial forms of neurodegenerative diseases code for products directly interacting with writers and erasers of the epigenome. Studies in postmortem human brains of affected individuals have also revealed global changes in DNA methylation and histone modifications. Overall, increasing evidence suggests that global changes of the epigenome occur in either familial or sporadic forms of neurodegenerative diseases and might be responsible for several of the symptoms accompanying such disorders. This notion is largely supported by studies in animal models showing that epigenetic drugs ameliorated both cognitive and motor symptoms, thereby opening a window for potential therapeutic interventions. There is increasing interest in understanding how changes in DNA methylation and histone modifications are reflected by those in gene expression and protein levels, and researchers are now searching for easily detectable surrogate epigenetic biomarkers in blood cells of affected individuals to be correlated with both exposure biomarkers and changes in gene expression. Recent epigenome-wide approaches are increasingly revealing the most significant epigenetic signatures and the genetic pathways that are dysregulated during disease progression, offering novel targets for therapeutic opportunities.
Hypothalamic α-synuclein and its relation to autonomic symptoms and neuroendocrine abnormalities in Parkinson disease
2021, Handbook of Clinical Neurology
Parkinson's disease (PD) is a complex neurodegenerative disorder presenting with defining motor features and a variable combination of nonmotor symptoms. There is growing evidence suggesting that hypothalamic involvement in PD may contribute to the pathogenesis of nonmotor symptoms. Initial neuropathologic studies demonstrated histologic involvement of hypothalamic nuclei by Lewy pathology, i.e., neuronal aggregates including Lewy bodies (round eosinophilic inclusions with a halo found in the neuronal perikarya) and other inclusions in neuronal processes such as Lewy neurites. Recent studies using more sensitive immunohistochemistry have shown that synuclein deposition is common in all hypothalamic nuclei and can happen at preclinical stages of the disease. Several neuropathologic changes, including synuclein deposition, neuronal loss, and adaptative morphologic changes, have been described in neurochemically defined specific hypothalamic cell populations with a potential role in the pathogenesis of nonmotor symptoms such as autonomic dysfunction, blood pressure control, circadian rhythms, sleep, and body weight regulation. The clinical implications of these hypothalamic neuropathologic changes are not fully understood and a direct clinical correlation may be challenging due to the multifactorial pathogenesis of the symptomatology and the additional involvement of other peripheral regulatory mechanisms. Future neuropathologic research using histological and functional assessments should establish the potential role of hypothalamic dysfunction on clinical burden, symptomatic therapies, and disease biomarkers in PD.

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

Article preview

Neuroscience Letters

Abstract

Highlights

Section snippets

Acknowledgments

References (24)

Alterations of T-lymphocyte populations in Parkinson's disease

Parkinsonism Relat. Disord.

Cytostatic drug treatment causes seeding of gene promoter methylation

Eur. J. Cancer.

The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research

Psychiatry Res.

Decreased expression of Bmal2 in patients with Parkinson's disease

Neurosci. Lett.

DNA methylation and mutation

Mutat. Res.

Uncoupling of promoter methylation and expression of Period1 in cervical cancer cells

Biochem. Biophys. Res. Commun.

Methylation analyses on promoters of mPER1, mPER2, and mCRY1 during perinatal development

Biochem. Biophys. Res. Commun

A pilot study for circadian gene disturbance in dementia patients

Neurosci. Lett.

The orphan nuclear receptor REV-ERB alpha controls circadian transcription within the positive limb of the mammalian circadian oscillator

Cell

A functional genomics strategy reveals Rora as a component of the mammalian circadian clock

Neuron

Parkinson's disease in China: prevalence in Beijing, Xian, and Shanghai

Lancet

Optimal primer design using the novel primer design program: MSP primer provides accurate methylation analysis of the ATM promoter ATM is not frequently methylated in cancer

Oncogene

Cited by (61)

Molecular crosstalk between circadian clock and NLRP3 inflammasome signaling in Parkinson's disease

Deciphering clock genes as emerging targets against aging

The effect of 3-Methyl-4-Nitrophenol on the early ovarian follicle development in mice by disrupting the clock genes expression

Roles of clock genes in the pathogenesis of Parkinson's disease

Epigenetics and cognitive disorders

Hypothalamic α-synuclein and its relation to autonomic symptoms and neuroendocrine abnormalities in Parkinson disease