TY - JOUR
T1 - Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo
AU - Cheng, Fubo
AU - Zheng, Wenxu
AU - Liu, Chang
AU - Barbuti, Peter Antony
AU - Yu-Taeger, Libo
AU - Casadei, Nicolas
AU - Huebener-Schmid, Jeannette
AU - Admard, Jakob
AU - Boldt, Karsten
AU - Junger, Katrin
AU - Ueffing, Marius
AU - Houlden, Henry
AU - Sharma, Manu
AU - Kruger, Rejko
AU - Grundmann-Hauser, Kathrin
AU - Ott, Thomas
AU - Riess, Olaf
N1 - Funding Information:
The research was partially supported by the fortüne junior grant, University of Tuebingen (FC: 2407-0-0), the Deutsche Forschungsgemeinschaft (DFG; OR: RI 682/19-1 AOBJ663994; MS: SH 599/6-1), the William N. and Bernice E. Bumpus Foundation (Innovation Award to P.A.B.), the Luxembourg Fond National de Recherche (FNR) within the PEARL (to R.K.) (FNR/P13/6682797), the INTER programme (to R.K. and P.A.B.) (INTER/LEIR/18/12719318), the MotaSYN (12719684), and the Deutsche Forschungsgemeinschaft (OR: NGS Competence Center Tübingen INST 37/1049-1).
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved.
PY - 2022/11/25
Y1 - 2022/11/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85142940102&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/36417521
U2 - 10.1126/sciadv.abq6324
DO - 10.1126/sciadv.abq6324
M3 - Article
C2 - 36417521
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 47
M1 - eabq6324
ER -