RRC ID 44655
著者 Giacopelli F, Cappato S, Tonachini L, Mura M, Di Lascio S, Fornasari D, Ravazzolo R, Bocciardi R.
タイトル Identification and characterization of regulatory elements in the promoter of ACVR1, the gene mutated in Fibrodysplasia Ossificans Progressiva.
ジャーナル Orphanet J Rare Dis
Abstract 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.
巻・号 8
ページ 145
公開日 2013-9-18
DOI 10.1186/1750-1172-8-145
PII 1750-1172-8-145
PMID 24047559
PMC PMC4015442
MeSH Activin Receptors, Type I / genetics* Bone Morphogenetic Protein 2 / genetics Cell Line, Tumor Computational Biology Electrophoretic Mobility Shift Assay HeLa Cells Humans Mutation Myositis Ossificans / genetics* Promoter Regions, Genetic / genetics* Reverse Transcriptase Polymerase Chain Reaction
IF 3.523
引用数 7
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL GENETICS & HEREDITY
リソース情報
ヒト・動物細胞 ATDC5(RCB0565)