Microarray Analysis of Treacher Collins Syndrome
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE10167 | GEO | 2008/01/15
SECONDARY ACCESSION(S): PRJNA108367
REPOSITORIES: GEO
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Project description:The object of this study was to identify genes transcriptionally upregulated and downregulated in response to Tcof1 haploin-sufficiency during mouse embryogensis Experiment Overall Design: Total RNA was extracted from 3 E8.5 wild-type and 3 E8.5 Tcof1+/- littermate embryos using the RNeasy Mini Protocol for Isolation of Total RNA from Animal Tissues (Qiagen) according to the manufacturerâs protocol. RNA quality and quantity was determined using the Bioanalyser. To generate targets for microarray analysis, total RNA (100 ng) from each wild-type and mutant embryo was amplified using Two-Cycle Target Labeling (Affymetrix) according to the manufacturerâs instructions. Biotinylated target cRNAs (20 μg) from the 3 wild-type and 3 Tcof1+/- embryos were hybridised to separate GeneChip® Mouse Genome 430 2.0 arrays (Affymetrix), following standard Affymetrix procedures.
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Project description:Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using human embryonic stem cell and Xenopus models, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest specification. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the craniofacial disorder Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination. Ribosome profiling and mRNA-Seq
2015-09-23 | E-GEOD-62247 | biostudies-arrayexpress
Project description:Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using a human embryonic stem cell model, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest cell formation. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the developmental disease Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination.
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Project description:Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using human embryonic stem cell and Xenopus models, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest specification. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the craniofacial disorder Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination.
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Project description:Metazoan development depends on accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation is brought about by global changes to chromatin architecture and transcriptional networks, yet whether other regulatory events support cell fate determination is less well understood. Using a human embryonic stem cell model, we identified the vertebrate-specific ubiquitin ligase Cul3KBTBD8 as an essential regulator of neural crest cell formation. Cul3KBTBD8 monoubiquitylates NOLC1 and its paralog TCOF1, whose mutation underlies the developmental disease Treacher Collins Syndrome that is characterized by a loss of cranial neural crest cells. Ubiquitylation of NOLC1 and TCOF1 drives formation of a platform that connects RNA polymerase I with ribosome modification enzymes, thereby altering the translational program of differentiating cells to support the generation of neural crest cells. We conclude that the dynamic regulation of ribosome function is an important feature of cell fate determination. Affymetrix assays were performed according to the manufacturer's directions on total RNA isolated from three independent samples of human embryonic stem cells (hESC) H1 cells or cells that had been differentiated into embryoid bodies for 6 days. Where indicated, hESC cells were transduced with control shRNA or shRNA targeting KBTBD8 prior to mRNA isolation. HUMAN GENE 1.0 ST ARRAY chips were used.
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Project description:Microarray Analysis of Treacher Collins Syndrome
| PRJNA108367 | ENA
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Project description:Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma. NB N1E-115 cells with wildtype, overexpression, knockdown of Tcof1.
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Project description:Heterozygous pathogenic variants in POLR1A were identified as the cause of Acrofacial Dysostosis, Cincinnati-type in 2015. Craniofacial anomalies reminiscent of Treacher Collins syndrome were the predominant phenotype observed in the first 3 affected individuals. We have subsequently identified 17 additional individuals with 12 unique (11 novel) heterozygous variants in POLR1A and observed numerous additional phenotypes including developmental delay, infantile spasms, and structural cardiac defects. To understand the pathogenesis of this pleiotropy, we created an allelic series of POLR1A using a combination of in vivo (mouse) and in vitro models. We describe distinct spatiotemporal requirements for Polr1a during mouse embryogenesis and identify a requirement for Polr1a for survival of pre migratory and migratory neural crest cells, forebrain precursors, and the second heart field. We used CRISPR/Cas9 to recapitulate two human alleles in mouse, demonstrating pathogenicity of one and likely benign nature of the other. Our work greatly expands the phenotype of human POLR1A-related disorders, provides new evidence of reduced penetrance and variable expression of POLR1A heterozygous variants, and demonstrates a multi-faceted approach to characterize and define pathogenicity of variants.
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