Cheng, Fubo;
Zheng, Wenxu;
Liu, Chang;
Barbuti, Peter Antony;
Yu-Taeger, Libo;
Casadei, Nicolas;
Huebener-Schmid, Jeannette;
... Riess, Olaf; + view all
(2022)
Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.
Science Advances
, 8
(47)
, Article eabq6324. 10.1126/sciadv.abq6324.
Preview |
Text
sciadv.abq6324.pdf - Published Version Download (4MB) | Preview |
Abstract
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.
| Type: | Article |
|---|---|
| Title: | Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.abq6324 |
| Publisher version: | https://doi.org/10.1126/sciadv.abq6324 |
| Language: | English |
| Additional information: | Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC) (https://creativecommons.org/licenses/by-nc/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161338 |
Archive Staff Only
 |
View Item |
