BACKGROUND: The ACVR1 gene encodes a type I receptor for bone morphogenetic 
proteins (BMPs). Mutations in the ACVR1 gene are associated with Fibrodysplasia 
Ossificans Progressiva (FOP), a rare and extremely disabling disorder 
characterized by congenital malformation of the great toes and progressive 
heterotopic endochondral ossification in muscles and other non-skeletal tissues. 
Several aspects of FOP pathophysiology are still poorly understood, including 
mechanisms regulating ACVR1 expression. This work aimed to identify regulatory 
elements that control ACVR1 gene transcription.
METHODS AND RESULTS: We first characterized the structure and composition of 
human ACVR1 gene transcripts by identifying the transcription start site, and 
then characterized a 2.9 kb upstream region. This region showed strong 
activating activity when tested by reporter gene assays in transfected cells. We 
identified specific elements within the 2.9 kb region that are important for 
transcription factor binding using deletion constructs, co-transfection 
experiments with plasmids expressing selected transcription factors, 
site-directed mutagenesis of consensus binding-site sequences, and by 
protein/DNA binding assays. We also characterized a GC-rich minimal promoter 
region containing binding sites for the Sp1 transcription factor.
CONCLUSIONS: Our results showed that several transcription factors such as 
Egr-1, Egr-2, ZBTB7A/LRF, and Hey1, regulate the ACVR1 promoter by binding to 
the -762/-308 region, which is essential to confer maximal transcriptional 
activity. The Sp1 transcription factor acts at the most proximal promoter 
segment upstream of the transcription start site. We observed significant 
differences in different cell types suggesting tissue specificity of 
transcriptional regulation. These findings provide novel insights into the 
molecular mechanisms that regulate expression of the ACVR1 gene and that could 
be targets of new strategies for future therapeutic treatments.