Neanderthal-derived variants shape craniofacial enhancer activity at a human disease locus
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PROVIDER: PRJNA1268529 | ENA |
REPOSITORIES: ENA
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Project description:Facial appearance is one of the most variable morphological traits in humans, influenced by both rare and common genetic variants that can impact facial form between individuals and in disease. Deletion of an enhancer cluster 1.45 megabases upstream of the SOX9 gene (EC1.45) results in Pierre Robin sequence, a human craniofacial disorder characterised by underdevelopment of the lower jaw and frequently associated with cleft palate. We reasoned that single nucleotide variants in EC1.45 may cause more subtle alterations to facial morphology. Here, we took advantage of recent human evolution, and the distinct morphology of the Neanderthal lower jaw, to investigate the impact of three Neanderthal-derived single nucleotide variants on EC1.45 function and jaw development. Utilising a dual enhancer-reporter system in zebrafish, we observed enhanced Neanderthal regulatory activity relative to the human orthologue during a specific developmental window. At this same stage, we show that EC1.45 appears to be selectively active in neural crest- derived progenitor cells which lie in close apposition with and are transcriptionally related to precartilaginous condensations that contribute to craniofacial skeletal development. To examine the potential consequences of increased SOX9 expression in this specific cellular population during jaw development, we overexpressed human SOX9 specifically in EC1.45-active cells and observed an increase in the volume of developing cartilaginous precursors. Taken together, our work implicates Neanderthal-derived variants in increased regulatory activity for a disease- associated enhancer with the potential to impact craniofacial skeletal development and jaw morphology across recent hominin evolution.
2025-08-11 | GSE298217 | GEO
Project description:Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a distal noncoding region of the human SOX9 gene causes the Pierre Robin sequence (PRS) characterized by the undersized lower jaw. Such a craniofacial-specific defect has been previously linked to enhancers transiently active in cranial neural crest cells (CNCCs). We demonstrate the PRS region also strongly regulates Sox9 in CNCC-derived Meckel's cartilage (MC), but not in limb cartilages. The MC-specific regulatory function of the PRS region cannot be attributed to the CNCC enhancers that have been inactivated in cartilages, but correlates with its MC-specific interactions with the Sox9 gene. By integrating the enhancer signatures and chromatin topology, we uncovered ~20,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings highlight the importance of lineage-dependent chromatin topology in instructing enhancer usage and provide critical insights for interpreting the genetic basis of craniofacial pathologies.
2023-01-04 | GSE185255 | GEO
Project description:Craniofacial and jaw bones have unique physiological specificities when compared to axial and appendicular bones. However, the molecular profile of the jaw osteoblast (OB) remains incomplete. The purpose of this study was to decipher the bone site-specific profile of transcription factors (TF) expressed in jaw osteoblasts in vivo. We accomplished this by performing RNA-seq analysis on flow-sorted osteoblasts isolated from jaw and tibial bones of 9-day-old (P9) transgenic Col1a1*2,3-GFP mice. This study demonstrated the feasibility of a new method to isolate pure OB populations and map their gene expression signature in the context of OB physiological environment, avoiding in vitro culture and its associated biases. Our results provided insights into the site-specific developmental pathways governing OB and identify new major OB regulators of bone physiology.
2022-02-14 | GSE186535 | GEO
Project description:Craniofacial dysmorphisms are among the most common birth defects. Proteasome mutations frequently result in craniofacial dysmorphisms including lower jaw malformations; however, the underlying mechanisms are unknown. Here we use a zebrafish proteasome subunit beta 1 (psmb1) mutant to define the cellular mechanisms underlying proteasome mutation-induced craniofacial dysmorphisms. psmb1 mutants exhibit a flattened ceratohyal and smaller Meckel’s and palatoquadrate cartilages. Ceratohyal flattening is a result of failed chondrocyte convergent extension, accompanied by reduced numbers of chondrocytes in the lower jaw due to defects in chondrocyte differentiation. Morphogenesis of craniofacial muscles and tendons is similarly perturbed. psmb1 mutants lack the hyohyal muscles and craniofacial tendons are shortened and disorganized. We additionally identify a critical period for proteasome function in craniofacial development, specifically during chondrocyte and muscle differentiation. psmb1 overexpression in sox10+ cells of mutant embryos rescued both cartilage and tendon phenotypes but induced only a partial rescue of the muscle phenotype, indicating that psmb1 is required in both tissue-autonomous and non-autonomous fashions during craniofacial development. Overall, our work demonstrates that psmb1 is required for craniofacial cartilage, tendon, and muscle differentiation and morphogenesis.
2024-07-12 | GSE243072 | GEO
Project description:Exposure to environmental contaminants can disrupt normal development of the early vertebrate skeleton. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) impairs craniofacial skeletal development across many vertebrate species and its effects are especially prominent in early life stages of fish. TCDD activates the aryl hydrocarbon receptor (AHR), a transcription factor that mediates most if not all TCDD responses. We investigated the transcriptional response in the developing zebrafish jaw following TCDD exposure using DNA microarrays. Zebrafish larvae were exposed to TCDD at 96 h postfertilization (hpf) and jaw cartilage tissue was harvested for microarray analysis at 1, 2, 4 and 12 h postexposure (hpe). Numerous chondrogenic transcripts were misregulated by TCDD in the jaw. Comparison of transcripts altered by TCDD in jaw with transcripts altered in embryonic heart showed that the transcriptional responses in the jaw and the heart were strikingly different. Sox9b, a critical chondrogenic transcription factor, was the most significantly reduced transcript in the jaw. We hypothesized that the TCDD reduction of sox9b expression plays an integral role in affecting formation of the embryonic jaw. Morpholino knock down of sox9b expression demonstrated that partial reduction of sox9b expression alone was sufficient to produce a TCDD-like jaw phenotype. Heterozygous sox9b deletion mutant embryos were sensitized to TCDD. Lastly, embryos injected with sox9b mRNA and then exposed to TCDD blocked TCDD-induced jaw toxicity in approximately 14% of sox9b-injected embryos. These results suggest that reduced sox9b expression in TCDD-exposed zebrafish embryos contributes to jaw malformation. Keywords: Time course
2008-11-01 | GSE11893 | GEO
Project description:While Neanderthals are extinct, fragments of their genome still persist in the genomes of contemporary humans. Here, we show that such Neanderthal-like sequences are not distributed randomly in contemporary human genomes. Specifically, while genome-wide frequency of Neanderthal-like sites is close to 6% in all out-of-Africa populations, genes involved in lipid catabolism contain large excess Neanderthal-like sequences in Europeans (24.3%), but not in Asians (12.4%). While lipid catabolism cannot be assayed in Neanderthals, we took advantage of genetic divergence between human populations, chimpanzees and Neanderthals to predict metabolic divergence expected from the observed excess of Neanderthal gene flow into Europeans. We confirmed predicted changes in lipid catabolism using hydrophobic metabolome measurements in the brain tissue and further linked these metabolic changes to gene expression divergence. 14 human and 6 chimpanzee samples were sequenced.
2014-03-31 | E-GEOD-45263 | biostudies-arrayexpress
Project description:While Neanderthals are extinct, fragments of their genome still persist in the genomes of contemporary humans. Here, we show that such Neanderthal-like sequences are not distributed randomly in contemporary human genomes. Specifically, while genome-wide frequency of Neanderthal-like sites is close to 6% in all out-of-Africa populations, genes involved in lipid catabolism contain large excess Neanderthal-like sequences in Europeans (24.3%), but not in Asians (12.4%). While lipid catabolism cannot be assayed in Neanderthals, we took advantage of genetic divergence between human populations, chimpanzees and Neanderthals to predict metabolic divergence expected from the observed excess of Neanderthal gene flow into Europeans. We confirmed predicted changes in lipid catabolism using hydrophobic metabolome measurements in the brain tissue and further linked these metabolic changes to gene expression divergence.
2014-03-31 | GSE45263 | GEO
Project description:Exposure to environmental contaminants can disrupt normal development of the early vertebrate skeleton. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) impairs craniofacial skeletal development across many vertebrate species and its effects are especially prominent in early life stages of fish. TCDD activates the aryl hydrocarbon receptor (AHR), a transcription factor that mediates most if not all TCDD responses. We investigated the transcriptional response in the developing zebrafish jaw following TCDD exposure using DNA microarrays. Zebrafish larvae were exposed to TCDD at 96 h postfertilization (hpf) and jaw cartilage tissue was harvested for microarray analysis at 1, 2, 4 and 12 h postexposure (hpe). Numerous chondrogenic transcripts were misregulated by TCDD in the jaw. Comparison of transcripts altered by TCDD in jaw with transcripts altered in embryonic heart showed that the transcriptional responses in the jaw and the heart were strikingly different. Sox9b, a critical chondrogenic transcription factor, was the most significantly reduced transcript in the jaw. We hypothesized that the TCDD reduction of sox9b expression plays an integral role in affecting formation of the embryonic jaw. Morpholino knock down of sox9b expression demonstrated that partial reduction of sox9b expression alone was sufficient to produce a TCDD-like jaw phenotype. Heterozygous sox9b deletion mutant embryos were sensitized to TCDD. Lastly, embryos injected with sox9b mRNA and then exposed to TCDD blocked TCDD-induced jaw toxicity in approximately 14% of sox9b-injected embryos. These results suggest that reduced sox9b expression in TCDD-exposed zebrafish embryos contributes to jaw malformation. Experiment Overall Design: Three independent replicate microarray time course experiments were performed comparing transcript levels between TCDD-exposed and control zebrafish. For each experiment, zebrafish were exposed to TCDD for 1 h starting at 96 hpf as described above. For each time point (97, 98, 100 and 108 hpf) and treatment jaw samples were pooled from 10 dissections for RNA isolation and hybridization with Affymetrix zebrafish arrays (Affymetrix, Santa Clara, CA). Each microarray contains roughly 14,900 probes corresponding to approximately 30% of the zebrafish genome. For each array, total RNA (1 µg) was isolated from 10 jaw microdissections with the QIAGEN RNeasy Mini kit following the manufacturerâs protocol (QIAGEN, Valencia, CA). The One-Cycle Target Labeling and Control Reagents kit was used to synthesize cDNA and biotinylated cRNA following the manufacturerâs protocol (Affymetrix, Santa Clara, CA). Biotin-labeled cRNA (15 µg) was fragmented and hybridized onto Affymetrix Zebrafish Genechip Arrays following the protocol in the Affymetrix Genechip Expression Analysis Technical Manual. Following hybdrization, the arrays were washed and stained with streptavidin-phycoerythrin on an Affymetrix Fluidics Station 400 using the protocol EukGE WS2v4. Arrays were scanned with an Agilent Gene Array Scanner.
2008-11-13 | E-GEOD-11893 | biostudies-arrayexpress
Project description:Analysis of gene expression in activation-tagged jaw-d mutant plants. Total RNA was extracted from the aerial parts of two weeks old jaw-d and control plants. Keywords: other
2003-07-09 | GSE518 | GEO