Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo

Fubo Cheng*, Wenxu Zheng, Chang Liu, Peter Antony Barbuti, Libo Yu-Taeger, Nicolas Casadei, Jeannette Huebener-Schmid, Jakob Admard, Karsten Boldt, Katrin Junger, Marius Ueffing, Henry Houlden, Manu Sharma, Rejko Kruger, Kathrin Grundmann-Hauser, Thomas Ott, Olaf Riess*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)eabq6324
JournalScience advances
Volume8
Issue number47
DOIs
Publication statusPublished - 25 Nov 2022

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