Single-cell genomics profiling of the endoderm of the mouse embryonic pharynx
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182136 | GEO | 2021/12/20
REPOSITORIES: GEO
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Project description:Maldevelopment of the pharyngeal endoderm, an embryonic tissue critical for patterning of the pharyngeal region and ensuing organogenesis, ultimately contributes to several classes of human developmental syndromes and disorders. Such syndromes are characterized by a spectrum of phenotypes that currently cannot be fully explained by known mutations or genetic variants due to gaps in characterization of critical drivers of normal and dysfunctional development. Despite the disease-relevance of pharyngeal endoderm, we still lack a comprehensive and integrative view of the molecular basis and gene regulatory networks (GRNs) driving pharyngeal endoderm development. To close this gap, we applied transcriptomic and chromatin accessibility single-cell sequencing technologies to generate a multi-omic developmental resource spanning pharyngeal endoderm patterning to the emergence of organ-specific epithelia in the developing mouse embryo. We identify novel cell-type specific gene regulation, distill GRN models that define developing organ domains, and characterize the role of an immunodeficiency-associated forkhead box transcription factor.
2021-12-20 | GSE182135 | GEO
Project description:Maldevelopment of the pharyngeal endoderm, an embryonic tissue critical for patterning of the pharyngeal region and ensuing organogenesis, ultimately contributes to several classes of human developmental syndromes and disorders. Such syndromes are characterized by a spectrum of phenotypes that currently cannot be fully explained by known mutations or genetic variants due to gaps in characterization of critical drivers of normal and dysfunctional development. Despite the disease-relevance of pharyngeal endoderm, we still lack a comprehensive and integrative view of the molecular basis and gene regulatory networks (GRNs) driving pharyngeal endoderm development. To close this gap, we applied transcriptomic and chromatin accessibility single-cell sequencing technologies to generate a multi-omic developmental resource spanning pharyngeal endoderm patterning to the emergence of organ-specific epithelia in the developing mouse embryo. We identify novel cell-type specific gene regulation, distill GRN models that define developing organ domains, and characterize the role of an immunodeficiency-associated forkhead box transcription factor.
2021-12-20 | GSE182134 | GEO
Project description:Single cell-based studies have revealed tremendous cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degree of plasticity during organogenesis. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including liver, pancreas, gallbladder, and extra-hepatic bile ducts. Experimental manipulation of various developmental signals in the mouse embryo underscored important cellular plasticity in this embryonic territory. This is also reflected in the existence of human genetic syndromes as well as congenital or environmentally-caused human malformations featuring multiorgan phenotypes in liver, pancreas and gallbladder. Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary, and pancreatic structures are not yet established. Here, we combine computational modelling approaches with genetic lineage tracing to assess the tissue dynamics accompanying the ontogeny of the hepato-pancreato-biliary organ system. We show that a multipotent progenitor domain persists at the border between liver and pancreas, even after pancreatic fate is specified, contributing to the formation of several organ derivatives, including the liver. Moreover, using single-cell RNA sequencing we define a specialized niche that possibly supports such extended cell fate plasticity.
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Project description:Developmental defects affecting the pharynx and derived tissues can be found in a variety of syndromes, including DiGeorge, 22q11 deletion, CHARGE and Otofaciocervical syndromes. The associated malformations and dysfunctions of pharynx-derived tissues precipitate phenotypes ranging from malformed features and endocrine disorders to severe immunodeficiency, some of which are associated with high morbidity or elaborate treatment and health care costs. While some of the developmental defects have been linked to mutations or single-nucleotide polymorphisms in transcription factors (TFs) or cis-regulatory elements (CREs), the origin of most pharynx-specific birth defects remain poorly understood and the underlying genetic causes as well as epigenetic context remain elusive. Unfortunately, restricted human tissue access, and discordance of genetic factor requirement and phenotypic penetrance of disease associated human mutations when modeled in mice, has prohibited detailed insights on the molecular basis of mentioned human diseases. Human pluripotent stem cells (hPSCs) could in principle allow for detailed a genetically tractable model to decipher the molecular logic of normal and impaired pharynx development. To unlock hPSC for investigation of pharyngeal malformations and ensuing syndromes, we have developed a differentiation protocol to generate human pharyngeal endoderm in vitro. We have applied multi-omic approaches to characterize the molecular logic of cell fate transitions and developed models of gene regulatory network activities.
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Project description:Developmental defects affecting the pharynx and derived tissues can be found in a variety of syndromes, including DiGeorge, 22q11 deletion, CHARGE and Otofaciocervical syndromes. The associated malformations and dysfunctions of pharynx-derived tissues precipitate phenotypes ranging from malformed features and endocrine disorders to severe immunodeficiency, some of which are associated with high morbidity or elaborate treatment and health care costs. While some of the developmental defects have been linked to mutations or single-nucleotide polymorphisms in transcription factors (TFs) or cis-regulatory elements (CREs), the origin of most pharynx-specific birth defects remain poorly understood and the underlying genetic causes as well as epigenetic context remain elusive. Unfortunately, restricted human tissue access, and discordance of genetic factor requirement and phenotypic penetrance of disease associated human mutations when modeled in mice, has prohibited detailed insights on the molecular basis of mentioned human diseases. Human pluripotent stem cells (hPSCs) could in principle allow for detailed a genetically tractable model to decipher the molecular logic of normal and impaired pharynx development. To unlock hPSC for investigation of pharyngeal malformations and ensuing syndromes, we have developed a differentiation protocol to generate human pharyngeal endoderm in vitro. We have applied multi-omic approaches to characterize the molecular logic of cell fate transitions and developed models of gene regulatory network activities.
2023-08-17 | GSE222439 | GEO
Project description:Developmental defects affecting the pharynx and derived tissues can be found in a variety of syndromes, including DiGeorge, 22q11 deletion, CHARGE and Otofaciocervical syndromes. The associated malformations and dysfunctions of pharynx-derived tissues precipitate phenotypes ranging from malformed features and endocrine disorders to severe immunodeficiency, some of which are associated with high morbidity or elaborate treatment and health care costs. While some of the developmental defects have been linked to mutations or single-nucleotide polymorphisms in transcription factors (TFs) or cis-regulatory elements (CREs), the origin of most pharynx-specific birth defects remain poorly understood and the underlying genetic causes as well as epigenetic context remain elusive. Unfortunately, restricted human tissue access, and discordance of genetic factor requirement and phenotypic penetrance of disease associated human mutations when modeled in mice, has prohibited detailed insights on the molecular basis of mentioned human diseases. Human pluripotent stem cells (hPSCs) could in principle allow for detailed a genetically tractable model to decipher the molecular logic of normal and impaired pharynx development. To unlock hPSC for investigation of pharyngeal malformations and ensuing syndromes, we have developed a differentiation protocol to generate human pharyngeal endoderm in vitro. We have applied multi-omic approaches to characterize the molecular logic of cell fate transitions and developed models of gene regulatory network activities.
2023-08-17 | GSE221616 | GEO
Project description:Developmental defects affecting the pharynx and derived tissues can be found in a variety of syndromes, including DiGeorge, 22q11 deletion, CHARGE and Otofaciocervical syndromes. The associated malformations and dysfunctions of pharynx-derived tissues precipitate phenotypes ranging from malformed features and endocrine disorders to severe immunodeficiency, some of which are associated with high morbidity or elaborate treatment and health care costs. While some of the developmental defects have been linked to mutations or single-nucleotide polymorphisms in transcription factors (TFs) or cis-regulatory elements (CREs), the origin of most pharynx-specific birth defects remain poorly understood and the underlying genetic causes as well as epigenetic context remain elusive. Unfortunately, restricted human tissue access, and discordance of genetic factor requirement and phenotypic penetrance of disease associated human mutations when modeled in mice, has prohibited detailed insights on the molecular basis of mentioned human diseases. Human pluripotent stem cells (hPSCs) could in principle allow for detailed a genetically tractable model to decipher the molecular logic of normal and impaired pharynx development. To unlock hPSC for investigation of pharyngeal malformations and ensuing syndromes, we have developed a differentiation protocol to generate human pharyngeal endoderm in vitro. We have applied multi-omic approaches to characterize the molecular logic of cell fate transitions and developed models of gene regulatory network activities.
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Project description:Developmental defects affecting the pharynx and derived tissues can be found in a variety of syndromes, including DiGeorge, 22q11 deletion, CHARGE and Otofaciocervical syndromes. The associated malformations and dysfunctions of pharynx-derived tissues precipitate phenotypes ranging from malformed features and endocrine disorders to severe immunodeficiency, some of which are associated with high morbidity or elaborate treatment and health care costs. While some of the developmental defects have been linked to mutations or single-nucleotide polymorphisms in transcription factors (TFs) or cis-regulatory elements (CREs), the origin of most pharynx-specific birth defects remain poorly understood and the underlying genetic causes as well as epigenetic context remain elusive. Unfortunately, restricted human tissue access, and discordance of genetic factor requirement and phenotypic penetrance of disease associated human mutations when modeled in mice, has prohibited detailed insights on the molecular basis of mentioned human diseases. Human pluripotent stem cells (hPSCs) could in principle allow for detailed a genetically tractable model to decipher the molecular logic of normal and impaired pharynx development. To unlock hPSC for investigation of pharyngeal malformations and ensuing syndromes, we have developed a differentiation protocol to generate human pharyngeal endoderm in vitro. We have applied multi-omic approaches to characterize the molecular logic of cell fate transitions and developed models of gene regulatory network activities.
2023-08-17 | GSE222442 | GEO
Project description:Normal commitment of the endoderm of the third pharyngeal pouch (3PP) is essential for the development and differentiation of the thymus. The aim of this study was to investigate the role of transcription factor HOXA3 in the development and differentiation of the third pharyngeal pouch endoderm from human embryonic stem cells (hESCs). 3PP endoderm (3PPE) was differentiated from hESC-derived definitive endoderm (DE) by mimicking developmental queues with Activin A, WNT3A, retinoic acid and BMP4. The function of 3PPE was assessed by further differentiating into functional thymic epithelial cells. The effect of HOXA3 inhibition on cells of 3PPE was subsequently investigated. A highly efficient approach for differentiating 3PPE cells has been developed and these cells expressed 3PPE related genes HOXA3, SIX1, PAX9 as well as EpCAM. 3PPE cells had a strong potential to develop into thymic epithelia which expressed both the cortical epithelial cell markers K8 and CD205, and the medullary epithelial cell markers K5 and AIRE, and also promoted T cell maturation. More importantly, transcription factor HOXA3 not only regulated the differentiation of 3PPE, but also had a crucial role for the proliferation and migration 3PPE cells. Our further investigation revealed that HOXA3 controlled the commitment and function of 3PPE through the regulation of the Wnt signaling pathway by EPHB2. Our results demonstrated that HOXA3 functioned as the on-off switch to regulate the development of hESC-derived 3PPE through EPHB2-mediated Wnt pathway, and our findings will provide new insights into studying the development of the third pharyngeal pouch and thymic organ in vitro and in vivo.
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