REST regulates DYRK1A transcription in a negative feedback loop.

DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) has been shown to be involved in learning and memory impairments in Alzheimer disease and Down syndrome. As a homolog of Drosophila minibrain gene, DYRK1A also plays important roles in neurodevelopment; however, the function and regulatory mechanism of DYRK1A in neurodevelopment remain elusive. REST (RE1 silencing transcription factor) plays vital roles in neuronal differentiation. Here, we found that REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp -833 to -815 of human DYRK1A promoter. The coordinated expression of DYRK1A and REST in mouse brain further supports the cross-interaction of DYRK1A and REST during neurodevelopment. Moreover, we showed that DYRK1A dosage imbalance reduced REST protein stability and transcriptional activity through facilitating ubiquitination and subsequent degradation of REST protein. Therefore, the regulation of DYRK1A by REST in a negative feedback loop suggests that DYRK1A and REST are closely related in neurodevelopment.