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The 8q24 cleft lip susceptibility locus is a remote Myc enhancer required for normal face morphology

ABSTRACT: A 640kb non-coding interval at 8q24 has been associated with an increased risk of non-syndromic cleft lip and palate (CLP) in humans, but the genes and pathways involved in this genetic susceptibility have remained elusive. With a large series of rearrangements engineered over the syntenic mouse region, we showed that this interval contains very remote cis-acting enhancers that control c-myc expression in the developing face. Deletion of this interval led to mild alteration of facial morphologies in mice and, sporadically, to CLP. At a molecular level, we identified mis-expression of several downstream genes, highlighting a combined impact on cranio-facial developmental network and general metabolic capacity. This dual molecular etiology may account for the prominent role to the 8q24 region in human facial dysmorphologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE52974 | GEO | 2014/04/03

SECONDARY ACCESSION(S): PRJNA230608

REPOSITORIES: GEO

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The 8q24 cleft lip susceptibility locus is a remote Myc enhancer required for normal face morphology

Project description:A 640kb non-coding interval at 8q24 has been associated with an increased risk of non-syndromic cleft lip and palate (CLP) in humans, but the genes and pathways involved in this genetic susceptibility have remained elusive. With a large series of rearrangements engineered over the syntenic mouse region, we showed that this interval contains very remote cis-acting enhancers that control c-myc expression in the developing face. Deletion of this interval led to mild alteration of facial morphologies in mice and, sporadically, to CLP. At a molecular level, we identified mis-expression of several downstream genes, highlighting a combined impact on cranio-facial developmental network and general metabolic capacity. This dual molecular etiology may account for the prominent role to the 8q24 region in human facial dysmorphologies. ChIP-seq and transcriptomics analysis in wt or/and mutant mice

2014-04-03 | E-GEOD-52974 | biostudies-arrayexpress

Expression analysis of prostate tissue on locus 8q24 part 1

Project description:Investigation on expression levels of normal tissue from prostate cancer patients on locus 8q24. The region chr8:127640000-129120000 is tiled with 60 nt probes at 10 nt interval (hg18)

2013-04-11 | GSE45920 | GEO

Transcription profiling by array of neonatal and children dermal fibroblasts isolated from cleft lip and adult dermal fibroblasts of breast and face

Project description:We measured expression profiles of skin fibroblasts harvested during lip cleft surgery of neonates (until 16 days after birth) and children (until 10 years after birth) and compared them to fibroblast isolated from adult skin of breast, scar, and face. We observed clear differences between the cleft and facial fibroblasts and the fibroblasts of breast, as the former originate from the neural crest. Further, we observed differences between adult face fibroblasts and children fibroblasts.

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Expression analysis of prostate tissue on locus 8q24 part 1

2013-04-11 | E-GEOD-45920 | biostudies-arrayexpress

CNV analysis of 869 individuals from the Philippines with cleft lip and/or cleft palate

Project description:Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well-established that both common and rare sequence variants contribute to the formation of CL/P, however, the contribution of copy number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed, however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our case cohort compared to controls, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR/Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

2022-12-01 | GSE212166 | GEO

Association between IRF6 and 8q24 polymorphisms and nonsyndromic cleft lip with or without cleft palate: Systematic review and meta-analysis.

Project description:BackgroundWe conducted a systematic review and meta-analysis of interferon regulatory factor 6 and 8q24 polymorphisms with nonsyndromic cleft lip with/without cleft palate (NSCL/P).MethodsData extraction was independently performed by two reviewers. Genotypic effects of four polymorphisms from 31 studies were pooled separately by ethnicity using a mixed-effect logit model with accounting for heterogeneity.ResultsFor rs2235371, AA and GA carried, respectively, 51% (95% confidence interval [CI], 37%-61%) and 42% (95% CI, 32%-50%) lower risks of NSCL/P than GG genotypes in Asians, but these genotypes were not significant in Caucasians. For rs2013162, only AA was significant, that is, carried 0.65 (95% CI, 0.52-0.82) times lower odds than CC in Caucasians but not for Asians. For rs642961, AA and GA genotypes, respectively, carried 2.47 (95% CI, 1.41-4.35) and 1.40 (95% CI, 1.12-1.75) times higher odds in Asian, and 2.03 (95% CI, 1.52-2.71) and 1.58 (95% CI, 1.37-1.82) times higher odds in Caucasians compare with GG genotypes. For rs987525, AA and CA genotypes carried 2.27 (95% CI, 1.43-3.60) and 1.34 (95% CI, 1.02-1.77) times higher odds in Asian, and 5.25 (95% CI, 3.98-6.91) and 2.13 (95% CI-1.82, 2.49) times higher odds in Caucasians, and 1.42 (95% CI, 1.10-1.82) and 1.28 (95% CI, 1.09-1.50) times higher odds in mixed ethnicities compared with CC genotypes. These variant effects remained significant based on applying Bonferroni corrected-thresholds, except in the mixed ethnicity.ConclusionWe show robust variant effects in NSCL/P. Considering them with other genes and risk factors might be useful to improve prediction of NSCL/P occurrence. Birth Defects Research (Part A) 106:773-788, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc.

| S-EPMC5095821 | biostudies-literature

Cleft lip and cleft palate (CL/P) in Esrp1 KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

Project description:To investigate the molecular mechanisms that lead to CL/P in Esrp1-/- mice, we performed RNA-Seq using RNAs collected from both epithelial cells and mesenchymal cells from control and Esrp1-/- embryos. We used a previously described method to separate facial ectoderm and mesenchyme from facial prominences at E12.0, a stage at which lip fusion is underway (Li and Williams, 2013). We collected pooled paired ectoderm and mesenchyme samples to obtain sufficient material for four replicates each of ectoderm and mesenchyme fractions from WT and Esrp1-/- embryos and prepared total RNA for RNA-Seq. We used paired end sequencing and obtained deep coverage with an average of 100 million read pairs per replicate. Preliminary analysis of transcripts per million (TPM) values in the RNA-Seq analysis from epithelial and mesenchymal control samples validated that they were derived from relatively pure populations of each cell type using a panel of standard epithelial and mesenchymal cell type-specific markers, including Esrp1

2020-02-07 | GSE144853 | GEO

CNV analysis of 140 Filipinos with Cleft Lip and/or Palate

Project description:Orofacial clefts are one of the most common birth defects, affecting 1-2 per 1000 births, and have a complex etiology. High-resolution array-based comparative genomic hybridization has increased the ability to detect copy number variants that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 non-syndromic cleft lip and palate cases and 43 cases with cleft palate only, we identified a heterozygous deletion of Isthmin 1 in one affected case, as well as a deletion in a second case which removes putative 3' regulatory information. Isthmin 1 is a strong candidate for clefting as it is expressed in orofacial structures derived from the first branchial arch and is also in the same synexpression group as fibroblast growth factor 8 and sprouty RTK signaling antagonist 1a and 2, all of which have been associated with clefting. Copy number variants affecting Isthmin 1 are exceedingly rare in control populations, and Isthmin 1 scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or CRISPR/Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM homeobox 8, itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from copy number variant identification of a candidate gene to functional validation in a vertebrate model system and reveals Isthmin 1 as both a new human clefting locus as well as a key craniofacial patterning gene.

2018-01-17 | GSE100845 | GEO

Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans.

Project description:In a recent genome-wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among nonsyndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, United States, and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving P < 10(-6) in the allelic transmission disequilibrium test (TDT) showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians.

| S-EPMC3615645 | biostudies-literature

Family-based study shows heterogeneity of a susceptibility locus on chromosome 8q24 for nonsyndromic cleft lip and palate.

Project description:BackgroundNonsyndromic cleft lip with or without cleft palate is a common birth defect. Although a number of susceptibility loci have been reported, replication has often been lacking. This is likely due, in part, to the heterogeneity of datasets and methodologies. Two independent genome-wide association studies of individuals of largely western European extraction have identified a possible susceptibility locus on 8q24.21.MethodsTo determine the overall effect of this locus, we genotyped six of the previously associated single nucleotide polymorphisms in our Hispanic and non-Hispanic white family-based datasets and evaluated them for linkage and association. In addition, we genotyped a large African American family with nonsyndromic cleft lip with or without cleft palate that we had previously mapped to the 8q21.3-24.12 region to test for linkage.ResultsThere was no evidence for linkage to this region in any of the three ethnic groups. Nevertheless, strong evidence for association was noted in the non-Hispanic white group, whereas none was detected in the Hispanic dataset.ConclusionThese results confirm the previously reported association and provide evidence suggesting that there is ethnically based heterogeneity for this locus.

| S-EPMC2861347 | biostudies-literature

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