Disruption ofSATB2or its long-rangecis-regulation by SOX9 causes a syndromic form of Pierre Robin sequence

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Heterozygous loss-of-function (LOF) mutations in the gene encoding the DNA-binding protein, SATB2, result in micrognathia and cleft palate in both humans and mice. In three unrelated individuals, we show that translocation breakpoints (BPs) up to 896 kb 3′ ofSATB2polyadenylation site cause a phenotype which is indistinguishable from that caused bySATB2LOF mutations. This syndrome comprises long nose, small mouth, micrognathia, cleft palate, arachnodactyly and intellectual disability. These BPs map to a gene desert betweenPLCL1andSATB2.We identified three putativecis-regulatory elements (CRE1–3) using a comparative genomic approach each of which would be placed intransrelative toSATB2by all three BPs. CRE1–3 each bind p300 and mono-methylated H3K4 consistent with enhancer function.In silicoanalysis suggested that CRE1–3 contain one or more conserved SOX9-binding sites, and this binding was confirmed using chromatin immunoprecipitation on cells derived from mouse embryonic pharyngeal arch. Interphase bacterial artificial chromosome fluorescencein situhybridization measurements in embryonic craniofacial tissues showed that the orthologous region in mice exhibitsSatb2expression-dependent chromatin decondensation consistent withSatb2being a target gene of CRE1–3. To assess theirin vivofunction, we made multiple stable reporter transgenic lines for each enhancer in zebrafish. CRE2 was shown to driveSATB2-like expression in the embryonic craniofacial region. This expression could be eliminated by mutating theSOX9-binding site of CRE2. These observations suggest thatSATB2andSOX9may be acting together via complexcis-regulation to coordinate the growth of the developing jaw.

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