Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo.
Fubo ChengWenxu ZhengChang LiuPeter Antony BarbutiLibo Yu-TaegerNicolas CasadeiJeannette HübenerJakob AdmardKarsten BoldtKatrin JungerMarius UeffingHenry HouldenManu SharmaRejko KrügerKathrin Grundmann-HauserThomas OttOlaf H RießPublished in: Science advances (2022)
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.
Keyphrases
- transcription factor
- binding protein
- white matter
- resting state
- poor prognosis
- genome wide identification
- endothelial cells
- copy number
- dna methylation
- functional connectivity
- dna binding
- gene expression
- cerebral ischemia
- endoplasmic reticulum stress
- induced pluripotent stem cells
- multiple sclerosis
- long non coding rna
- cell proliferation
- pluripotent stem cells
- mouse model
- cell death
- small molecule
- protein protein
- genome wide analysis
- signaling pathway
- subarachnoid hemorrhage