The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA939357 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23635030.fastq.gz | Fastqsanger.gz | |||
| SRR23635031.fastq.gz | Fastqsanger.gz | |||
| SRR23635032.fastq.gz | Fastqsanger.gz | |||
| SRR23635033.fastq.gz | Fastqsanger.gz | |||
| SRR23635448_1.fastq.gz | Fastqsanger.gz |
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Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
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Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA-sequencing reveals that loss of Tet2/3 impaired chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides novel insights into understanding craniofacial development and CFM pathogenesis.
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Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here we employ zebrafish model to investigate the mechanism of CFM pathogenesis. In early embryos, tet2 and tet3 are highly expressed and are essential for pharyngeal cartilage development. Single-cell RNA sequencing and genetic analyses reveal that loss of Tet2/3 impaired chondrocyte differentiation largely due to insufficient BMP signaling. Mechanistically, Tet2/3-mediated 5-hydroxymethylcytosine modification allows the 5-hydroxymethylcytosine “reader”, Sall4, to specifically bind the bmp4 promoter, thereby promoting bmp4 expression and enabling efficient BMP signaling. These findings indicate the TET-BMP regulatory axis via 5-hydroxymethylcytosine to be critical for pharyngeal cartilage development. Whole-exome sequencing of CFM patient samples show that single nucleotide polymorphisms in TET and BMP pathway genes increase the risk of CFM. Collectively, our study provides novel insights into understanding craniofacial development and CFM pathogenesis.
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Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here we employ zebrafish model to investigate the mechanism of CFM pathogenesis. In early embryos, tet2 and tet3 are highly expressed and are essential for pharyngeal cartilage development. Single-cell RNA sequencing and genetic analyses reveal that loss of Tet2/3 impaired chondrocyte differentiation largely due to insufficient BMP signaling. Mechanistically, Tet2/3-mediated 5-hydroxymethylcytosine modification allows the 5-hydroxymethylcytosine “reader”, Sall4, to specifically bind the bmp4 promoter, thereby promoting bmp4 expression and enabling efficient BMP signaling. These findings indicate the TET-BMP regulatory axis via 5-hydroxymethylcytosine to be critical for pharyngeal cartilage development. Whole-exome sequencing of CFM patient samples show that single nucleotide polymorphisms in TET and BMP pathway genes increase the risk of CFM. Collectively, our study provides novel insights into understanding craniofacial development and CFM pathogenesis.
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Project description:Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here we employ zebrafish model to investigate the mechanism of CFM pathogenesis. In early embryos, tet2 and tet3 are highly expressed and are essential for pharyngeal cartilage development. Single-cell RNA sequencing and genetic analyses reveal that loss of Tet2/3 impaired chondrocyte differentiation largely due to insufficient BMP signaling. Mechanistically, Tet2/3-mediated 5-hydroxymethylcytosine modification allows the 5-hydroxymethylcytosine “reader”, Sall4, to specifically bind the bmp4 promoter, thereby promoting bmp4 expression and enabling efficient BMP signaling. These findings indicate the TET-BMP regulatory axis via 5-hydroxymethylcytosine to be critical for pharyngeal cartilage development. Whole-exome sequencing of CFM patient samples show that single nucleotide polymorphisms in TET and BMP pathway genes increase the risk of CFM. Collectively, our study provides novel insights into understanding craniofacial development and CFM pathogenesis.
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Project description:SALL4 is a critical transcription factor involved in early embryonic development. While its role in pluripotency remains debated, SALL4 has been implicated in various lineage specification processes. The neural crest-derived anomalies observed in individuals with SALL4 haploinsufficiency, combined with high SALL4 expression observed in mouse cranial neural crest cells (CNCCs), suggest a role for this transcription factor in CNCC specification and craniofacial development, however, this has not yet been investigated. Moreover, while SALL4 is an established interactor of the NuRD chromatin remodeling complex, recent mass-spectrometry studies from our group have suggested a novel interaction between SALL4 and the BAF complex during human CNCC specification. Here, we investigate the functional significance of this interaction and the broader role of SALL4 in CNCC development. We generated a human iPSC line with SALL4 heterozygous knock-out to model the haploinsufficient variants observed in SALL4-associated human developmental syndromes. Our findings reveal that the SALL4A isoform directly interacts with the BAF subunit DPF2 via its zinc-finger-cluster-3 and -4 domain. During early CNCC specification, SALL4A is required for BAF-mediated chromatin remodeling at enhancers essential for CNCC fate. In the absence of SALL4A, cells progress normally through the neuroectodermal stage but fail to specify into CNCCs, as CNCC lineage-specific enhancers remain repressed. Moreover, we demonstrate that the SALL4B isoform cannot compensate for SALL4A loss, as it lacks the zinc-finger-3 domain necessary for BAF interaction. These findings establish a novel role for SALL4A in CNCC specification by regulating BAF-mediated enhancer activation, shedding light on the molecular mechanisms underlying SALL4-associated craniofacial anomalies.
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