TY - JOUR
T1 - Regulation of Αlpha-Synuclein Gene (SNCA) by Epigenetic Modifier TET1 in Parkinson Disease
AU - Guhathakurta, Subhrangshu
AU - Song, Min Kyung
AU - Basu, Sambuddha
AU - Je, Goun
AU - Cristovao, Ana Clara
AU - Kim, Yoon Seong
N1 - Funding Information: This work was supported by the National Institute of Health (grant number 5R21NS088923-02); and Michael J Fox Foundation (Target Advancement award 2015) awarded to YSK. Authors gratefully acknowledge (a) Human Brain and Spinal Fluid Resource Centre, UCLA, under NIH Neurobio bank; (b) Brain Endowment Bank of University of Miami, Miller School of Medicine; (c) Parkinson’s UK Brain Bank, and (d) Harvard Brain Tissue Resource Centre for providing all the human postmortem brain samples. Funding Information: • Fund/Grant Support: This work was supported by the National Institute of Health (grant number 5R21NS088923-02); and Michael J Fox Foundation (Target Advancement award 2015) awarded to YSK. • Research Ethics: All human postmortem brain samples were procured from NIH Neurobiobank and were used in accordance with the princi-ples of the Declaration of Helsinki of the World Medical Association. • Conflict of Interest: No potential conflict of interest relevant to this article was reported. Publisher Copyright: Copyright © 2022 Korean Continence Society.
PY - 2022/11
Y1 - 2022/11
N2 - Purpose: Deregulation of SNCA encoding α-synuclein (α-SYN) has been associated with both the familial and sporadic forms of Parkinson disease (PD). Epigenetic regulation plays a crucial role in PD. The intron1 of SNCA harbors a large unmethylated CpG island. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1), a CpG island binding protein, can repress gene expression by occupying hypomethylated CpG-rich promoters, and therefore SNCA could be a target for TET1. We investigated whether TET1 binds to SNCA-intron1 and regulates gene expression. Methods: The dopaminergic neuronal cell line, ReNcell VM, was used. Reverse transcription-polymerase chain reaction (RT-PCR), real time-quantitative PCR, Western blot, dot-blot, and Chromatin immunoprecipitation were conducted. The substantia nigra tissues of postmortem PD samples were used to confirm the level of TET1 expression. Results: In the human dopaminergic cell line, ReNcell VM, overexpression of the DNA-binding domain of TET1 (TET1-CXXC) led to significant repression of α-SYN. On the contrary, knocking down of TET1 led to significantly higher expression of α-SYN. However, overexpression of the DNA-hydroxymethylating catalytic domain of TET1 failed to change the expression of α-SYN. Altogether, we showed that TET1 is a repressor for SNCA, and a CXXC domain of TET1 is the primary mediator for this repressive action independent of its hydroxymethylation activity. TET1 levels in PD patients are significantly lower than that in the controls. Conclusions: We identified that TET1 acts as a repressor for SNCA by binding the intron1 regions of the gene. As a high level of α-SYN is strongly implicated in the pathogenesis of PD, discovering a repressor for the gene encoding α-SYN is highly important for developing novel therapeutic strategies for the disease.
AB - Purpose: Deregulation of SNCA encoding α-synuclein (α-SYN) has been associated with both the familial and sporadic forms of Parkinson disease (PD). Epigenetic regulation plays a crucial role in PD. The intron1 of SNCA harbors a large unmethylated CpG island. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1), a CpG island binding protein, can repress gene expression by occupying hypomethylated CpG-rich promoters, and therefore SNCA could be a target for TET1. We investigated whether TET1 binds to SNCA-intron1 and regulates gene expression. Methods: The dopaminergic neuronal cell line, ReNcell VM, was used. Reverse transcription-polymerase chain reaction (RT-PCR), real time-quantitative PCR, Western blot, dot-blot, and Chromatin immunoprecipitation were conducted. The substantia nigra tissues of postmortem PD samples were used to confirm the level of TET1 expression. Results: In the human dopaminergic cell line, ReNcell VM, overexpression of the DNA-binding domain of TET1 (TET1-CXXC) led to significant repression of α-SYN. On the contrary, knocking down of TET1 led to significantly higher expression of α-SYN. However, overexpression of the DNA-hydroxymethylating catalytic domain of TET1 failed to change the expression of α-SYN. Altogether, we showed that TET1 is a repressor for SNCA, and a CXXC domain of TET1 is the primary mediator for this repressive action independent of its hydroxymethylation activity. TET1 levels in PD patients are significantly lower than that in the controls. Conclusions: We identified that TET1 acts as a repressor for SNCA by binding the intron1 regions of the gene. As a high level of α-SYN is strongly implicated in the pathogenesis of PD, discovering a repressor for the gene encoding α-SYN is highly important for developing novel therapeutic strategies for the disease.
KW - Parkinson disease
KW - Repressor
KW - TET1
KW - Αlpha-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85146291826&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85146291826&partnerID=8YFLogxK
U2 - https://doi.org/10.5213/inj.2222206.103
DO - https://doi.org/10.5213/inj.2222206.103
M3 - Article
SN - 2093-4777
VL - 26
SP - S85-S93
JO - International Neurourology Journal
JF - International Neurourology Journal
IS - S2
ER -