Human Molecular Genetics Advance Access originally published online on April 4, 2007
Human Molecular Genetics 2007 16(10):1143-1156; doi:10.1093/hmg/ddm061
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SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway
Stankiewicz1,31 Department of Molecular and Human Genetics, 2 Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Rm. 604B, Houston, TX 77030, USA, 3 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland and 4 Texas Children’s Hospital, Houston, TX, USA
* To whom correspondence should be addressed. Tel: +1 7137986530; Fax: +1 7137985073; Email: jlupski{at}bcm.tmc.edu
Received January 8, 2007; Revised March 7, 2007; Accepted March 13, 2007
SOX9 is a temporal and tissue-specific transcription factor involved in male sexual development and bone formation. Haploinsufficiency of SOX9 is known to cause campomelic dysplasia (CD). CD cases without SOX9 coding region mutations have been described in association with translocations that have breakpoints mapping as far as 932 kb upstream from the gene. These rearrangements suggest that position effects acting from a great distance regulate SOX9 gene expression. Studies of one such case (900 kb upstream to SOX9) have led to the delineation of a potential 2.1 kb cis-acting regulatory element 1.1 Mb upstream of SOX9, termed SOX9cre1. We investigated the role of this putative regulator in SOX9 expression. SOX9cre1 increases the activity of a minimal SOX9 promoter in reporter constructs in a dose-dependent and tissue-specific manner, consistent with an enhancer role. In silico studies identify a putative binding site within SOX9cre1 for GLI1, a downstream mediator of sonic hedgehog (SHH). Furthermore, the stimulation of primary human chondrocyte cells in culture with SHH increases endogenous SOX9 expression 3-fold. Electrophoresis mobility shift assay (EMSA) studies that demonstrate physical interactions between the GLI1 transcription factor and a putative binding site within SOX9cre1, as well as experiments in which reporter constructs are co-transfected with GLI1, suggest a direct interaction between GLI1 and SOX9cre1. GLI1-SOX9cre1 interactions are verified in chromatin immunoprecipitation experiments. These data support a direct molecular link between the Hh signaling pathway and SOX9 regulation, wherein SHH stimulates SOX9 through its mediator GLI1, and are consistent with a mechanism of SOX9 regulation through distal chromatin interactions.
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