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Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro.
FEBS J. 2014 Apr; 281(8):2088-96.FJ

Abstract

Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (NSC) proliferation and alterations in DNA methylation may be involved. The aim of the present study was to characterize the effects of Hcy on DNA methylation in NSCs, and to explore how Hcy-induced changes in DNA methylation patterns affect NSC proliferation. We found that D,L-Hcy (30-1000 μm) but not L-cysteine inhibited cell proliferation and reduced levels of global DNA methylation in NSCs from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in S-adenosylhomocysteine (SAH), a decrease in the ratio of S-adenosylmethionine (SAM) to SAH, and a reduction in protein expression of the DNA methyltransferases DNMT1, DNMT3a and DNMT3b and their enzymatic activity. Moreover, the DNMT inhibitor zebularine reduced the global DNA methylation level and inhibited NSC proliferation. Our results suggest that alterations in DNA methylation may be an important mechanism by which high levels of Hcy inhibit NSC viability in vitro. Hcy-induced DNA hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of SAM and SAH, or their protein expression levels. Our results also suggest that Hcy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of NSC proliferation and alterations in DNA methylation.

Authors+Show Affiliations

Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24612628

Citation

Lin, Ningning, et al. "Homocysteine Induces Cytotoxicity and Proliferation Inhibition in Neural Stem Cells Via DNA Methylation in Vitro." The FEBS Journal, vol. 281, no. 8, 2014, pp. 2088-96.
Lin N, Qin S, Luo S, et al. Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro. FEBS J. 2014;281(8):2088-96.
Lin, N., Qin, S., Luo, S., Cui, S., Huang, G., & Zhang, X. (2014). Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro. The FEBS Journal, 281(8), 2088-96. https://doi.org/10.1111/febs.12764
Lin N, et al. Homocysteine Induces Cytotoxicity and Proliferation Inhibition in Neural Stem Cells Via DNA Methylation in Vitro. FEBS J. 2014;281(8):2088-96. PubMed PMID: 24612628.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro. AU - Lin,Ningning, AU - Qin,Shanchun, AU - Luo,Suhui, AU - Cui,Shanshan, AU - Huang,Guowei, AU - Zhang,Xumei, Y1 - 2014/03/17/ PY - 2013/10/21/received PY - 2014/01/12/revised PY - 2014/02/20/accepted PY - 2014/3/12/entrez PY - 2014/3/13/pubmed PY - 2014/6/12/medline KW - DNA methylation KW - DNA methyltransferases KW - homocysteine KW - neural stem cells KW - proliferation SP - 2088 EP - 96 JF - The FEBS journal JO - FEBS J. VL - 281 IS - 8 N2 - Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (NSC) proliferation and alterations in DNA methylation may be involved. The aim of the present study was to characterize the effects of Hcy on DNA methylation in NSCs, and to explore how Hcy-induced changes in DNA methylation patterns affect NSC proliferation. We found that D,L-Hcy (30-1000 μm) but not L-cysteine inhibited cell proliferation and reduced levels of global DNA methylation in NSCs from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in S-adenosylhomocysteine (SAH), a decrease in the ratio of S-adenosylmethionine (SAM) to SAH, and a reduction in protein expression of the DNA methyltransferases DNMT1, DNMT3a and DNMT3b and their enzymatic activity. Moreover, the DNMT inhibitor zebularine reduced the global DNA methylation level and inhibited NSC proliferation. Our results suggest that alterations in DNA methylation may be an important mechanism by which high levels of Hcy inhibit NSC viability in vitro. Hcy-induced DNA hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of SAM and SAH, or their protein expression levels. Our results also suggest that Hcy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of NSC proliferation and alterations in DNA methylation. SN - 1742-4658 UR - https://www.unboundmedicine.com/medline/citation/24612628/Homocysteine_induces_cytotoxicity_and_proliferation_inhibition_in_neural_stem_cells_via_DNA_methylation_in_vitro_ L2 - https://doi.org/10.1111/febs.12764 DB - PRIME DP - Unbound Medicine ER -