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Global DNA methylation profiling of manganese-exposed human neuroblastoma SH-SY5Y cells reveals epigenetic alterations in Parkinson’s disease-associated genes

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Abstract

Manganese (Mn) is an essential trace element required for optimal functioning of cellular biochemical pathways in the central nervous system. Elevated exposure to Mn through environmental and occupational exposure can cause neurotoxic effects resulting in manganism, a condition with clinical symptoms identical to idiopathic Parkinson’s disease. Epigenetics is now recognized as a biological mechanism involved in the etiology of various diseases. Here, we investigated the role of DNA methylation alterations induced by chronic Mn (100 µM) exposure in human neuroblastoma (SH-SY5Y) cells in relevance to Parkinson’s disease. A combined analysis of DNA methylation and gene expression data for Parkinson’s disease-associated genes was carried out. Whole-genome bisulfite conversion and sequencing indicate epigenetic perturbation of key genes involved in biological processes associated with neuronal cell health. Integration of DNA methylation data with gene expression reveals epigenetic alterations to PINK1, PARK2 and TH genes that play critical roles in the onset of Parkinsonism. The present study suggests that Mn-induced alteration of DNA methylation of PINK1–PARK2 may influence mitochondrial function and promote Parkinsonism. Our findings provide a basis to further explore and validate the epigenetic basis of Mn-induced neurotoxicity .

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Abbreviations

APC:

Adenomatous polyposis coli

ATP2B2:

ATPase plasma membrane Ca2+ transporting 2

CXXC1:

DNA-binding protein with PHD finger and CXXC domain

DLK1:

Delta-like 1 homolog (Drosophila)

DRD2:

Dopamine receptor D2

GBE1:

1,4-Alpha-glucan branching enzyme

Mn:

Manganese

NRXN3:

Neurexin 3

NSF:

N-Ethylmaleimide-sensitive factor

PAN2:

Poly(A)-specific ribonuclease subunit

PARK2:

Parkin RBR E3 ubiquitin protein ligase

PINK1:

PTEN-induced putative kinase 1

PPI:

Protein–protein interaction

SLC25A4:

Solute carrier family 25 member 4

SNCA:

Synuclein alpha

STUB1:

STIP1 homology and U-box containing protein 1

TH:

Tyrosine hydroxylase

VDAC:

Voltage-dependent anion-selective channel protein 1

WGBS:

Whole-genome bisulfite conversion and sequencing

YWHAZ:

Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta

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Acknowledgements

The authors are thankful to CSIR-NEERI, Nagpur, India, for providing the necessary facilities. Authors are grateful to integrated NextGen approaches in health, disease and environmental toxicity (INDEPTH) networking project (BSC 0111) for providing necessary funding and Institutional Knowledge Resource Center (KRC) No. KRC/2016/SEP/EHD/2.

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Authors and Affiliations

  1. Environmental Health Division, CSIR - National Environmental Engineering Research Institute (NEERI), Nagpur, 440020, India

    Prashant Tarale, Saravanadevi Sivanesan, Atul P. Daiwile, Amit Bafana, Pravin K. Naoghare & Krishnamurthi Kannan

  2. Visvesvaraya National Institute of Technology (VNIT), Nagpur, 440010, India

    Tapan Chakrabarti

  3. Schools of Biosciences, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, UK

    Prashant Tarale & Reinhard Stöger

  4. Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research (IITR), Lucknow, 226001, India

    Devendra Parmar

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  1. Prashant Tarale
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Correspondence to Saravanadevi Sivanesan.

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Tarale, P., Sivanesan, S., Daiwile, A.P. et al. Global DNA methylation profiling of manganese-exposed human neuroblastoma SH-SY5Y cells reveals epigenetic alterations in Parkinson’s disease-associated genes. Arch Toxicol 91, 2629–2641 (2017). https://doi.org/10.1007/s00204-016-1899-0

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