Article (Scientific journals)
Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.
Cheng, Fubo; Zheng, Wenxu; Liu, Chang et al.
2022In Science Advances, 8 (47), p. 6324
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Keywords :
Humans; alpha-Synuclein/genetics; Apoptosis Regulatory Proteins/metabolism; Brain/metabolism; DNA-Binding Proteins/metabolism; Introns/genetics; Parkinson Disease/metabolism; Polymorphism, Single Nucleotide; Regulatory Sequences, Nucleic Acid
Abstract :
[en] Evidence from patients with Parkinson's disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA. THAP1 controls SNCA intronic enhancers' activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment-dependent activities and form enhancer clusters similar to "super-enhancers" in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.
Disciplines :
Neurology
Author, co-author :
Cheng, Fubo
Zheng, Wenxu
Liu, Chang
Barbuti, Peter Antony
Yu-Taeger, Libo
Casadei, Nicolas
Huebener-Schmid, Jeannette
Admard, Jakob
Boldt, Karsten
Junger, Katrin
Ueffing, Marius
Houlden, Henry
Sharma, Manu
Krüger, Rejko ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Grundmann-Hauser, Kathrin
Ott, Thomas
Riess, Olaf
More authors (7 more) Less
External co-authors :
yes
Language :
English
Title :
Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.
Publication date :
23 November 2022
Journal title :
Science Advances
ISSN :
2375-2548
Publisher :
American Association for the Advancement of Science (AAAS), Washington, United States - District of Columbia
Volume :
8
Issue :
47
Pages :
eabq6324
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 16 January 2023

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