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The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development

ABSTRACT: 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.

ORGANISM(S): Danio rerio

PROVIDER: GSE226184 | GEO | 2024/03/04

REPOSITORIES: GEO

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The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development

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.

2024-02-02 | PXD049147 |

The TET-BMP regulatory axis in pathogenesis of CFM [scRNA]

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.

2024-03-04 | GSE226183 | GEO

The TET-BMP regulatory axis in pathogenesis of CFM [RNA-Seq]

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.

2024-03-04 | GSE226182 | GEO

The TET-BMP regulatory axis in pathogenesis of CFM [hMeDIPseq]

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.

2024-03-04 | GSE226180 | GEO

The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development

Project description:The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development

| PRJNA939357 | ENA

Gabriella Miller Kids First Pediatric Research Program in Craniofacial Microsomia

Project description:The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). <div> </div><div>All of the WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. </div><div> </div><div>Craniofacial microsomia (CFM), also termed hemifacial microsomia or oculo-auricular-vertebral spectrum, is the third most common congenital craniofacial condition. CFM comprises a variable phenotype and the most common features include malformations of the ear (i.e. microtia) and lower jaw (i.e. mandibular hypoplasia) on one or both sides. Microtia in the absence of other anomalies is believed to represent the mildest form of CFM. The cause of CFM is unknown for most affected individuals. We have established a cohort through previous studies and collected DNA to identify the genetic contributions to CFM, which could facilitate diagnosis, tailored treatments and guide prevention strategies. Successful completion of this proposal will advance knowledge in the genetic architecture of susceptibility to CFM and will provide insight about the biological mechanisms underlying craniofacial development. The results from this study have the potential to further research on the etiology of other craniofacial conditions, and the pathogenesis of typical and atypical craniofacial development. </div><div><br></div>

| phs002130 | dbGaP

Combined deficiency of Tet1 and Tet2 is compatible with development but leads to epigenetic instability

Project description:Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 and Tet2 mediate 5hmC generation in mouse embryonic stem cells (ESCs) and various embryonic and adult tissues. To investigate the effects of combined deficiency of Tet1 and Tet2 on pluripotency and development, we have generated Tet1 and Tet2 double knockout (DKO) ESCs and mice. DKO ESCs were depleted of 5hmC, but remained pluripotent with subtle defects in differentiation and changes in gene expression. Double mutant embryos and chimeras exhibited mid-gestation defects and postnatal DKO mice displayed partially penetrant neonatal lethality and stochastic perturbation of imprinting. Viable DKO animals developed normally to adulthood but had reduced 5hmC level, increased 5mC level and lacked 5hmC in germ cells. Nevertheless, DKO mice of both sexes were fertile with females having smaller ovaries and reduced fertility. Our data suggest that both Tet1 and Tet2 contribute to 5hmC levels during development. Their combined loss does not block differentiation and embryogenesis, but leads to partially penetrant embryonic and perinatal abnormalities and compromised viability. Moreover, the presence of substantial levels of 5hmC in DKO embryos and adult mice suggests a significant contribution of Tet3 in hydroxylation of 5mC during development. Methylation patterns in tissue samples from a series of wt and Tet1/Tet2 DKO embryos, neonates and adults were generated using methylated DNA immunoprecipitation with antibodies against 5mC (MeDIP) and 5hmC (hMeDIP) followed by deep sequencing.

2013-02-01 | E-GEOD-42396 | biostudies-arrayexpress

Bone morphogenetic protein 4 in human saliva during orthodontic therapy

Project description:In orthodontic therapy periodontal tissue responds to mechanical stimuli by bone remodeling mediated by specific molecules involved in periodontal regeneration and homeostasis. The resulting changes are reflected in the salivary proteome that is emerging as a valuable diagnostic tool. We analyzed the changes of saliva proteome during orthodontic tooth movement in 12 healthy male patients, presented with malocclusion treated by placement of fixed orthodontic appliance. Six patients with identical dental pathology, but no orthodontic therapy were used as control samples. Saliva was collected a day before, immediately after, and 2, 7 and 30 days after the placement of the fixed orthodontic appliance and analyzed by LC-MS. Total of 198 proteins were identified and classified on the basis of their functional characteristics. Proteins involved in bone remodeling, inflammation and healing were detected mostly 30 days after placement of the fixed orthodontic appliance. At this time point, Bone morphogenetic protein 4 emerged as a central player in the ongoing dental bone remodeling. Besides BMP4, BMP antagonists: BMP Binding Endothelial Regulator (BMPER), Insulin-like growth factor-binding protein 3 (IGFBP3), Cytoskeleton-associated protein 4 (CKAP4) and Fibroblast growth factor 5 (FGF5), were also identified. Presence of BMP4 in human saliva 30 days after the placement of orthodontic fixed appliance was confirmed by ELISA and concentration of BMP4 was 3.2 pg/ml. To date, there is no published data on the presence of BMP molecules or their antagonists in saliva or the gingival cervical fluid, regardless of different orthodontic treatments or disease. BMP4 is involved not only in orthodontic treatment, but also in processes involving tooth development and homeostasis. Therefore, a better understanding of its networks in bone remodeling during OTM is heralded.

2021-09-09 | PXD016481 | Pride

Cell fate decision by a morphogen-transcription factor-chromatin modifier axis

Project description:Bulk RNA-sequences show the differences upon primitive endoderm cell related gene expression between JGES induced somatic cell reprogramming with or without BMP4 treatment, and between WT-SALL4 or delN12-SALL4 induced transdifferentiation from E13.5 mouse embryonic fibroblasts, primitive endoderm cell related gene are from our single cell RNA sequence data So as to estimate the chromatin remodeling differences between SALL4-WT and SALL4-delN12 during single factor induced PrE formation, we performed Tn5 dependent ATAC-sequence to compare the open and close chromatin of the two group. In order to identify the bingding differences of SALL4 and H3K27ac level diversity between SALL4-WT and SALL4-delN12 on PrE related genes, wo performed CUTandTAG experiments. Single cell analysis provides clarity unattainable with bulk approaches. Here we apply single cell RNA-seq to a newly established mouse somatic cell reprogramming system with or without BMP4 treatment at Day 7, this reprogramming system are induced by four transcriptional factors Jdp2-Glis1-Esrrb-Sall4 or JGES and cultured in iCD3. We first show that cells could be clustered into four group, primitive endoderm cell like cells, pluripotent cells, endothelial cells, and intermediate state cells which are hard to be clarified, after BMP4 treatment, a placenta-like state arise, the percentage of endothelial cells and primitive endoderm cell like cells increase and pluripotent cells decrease sharply. Our results not only show the ability of JGES and BMP4 in different cell lineage induction but also provide a model to explore mechanisms of first and second cell lineage decision during early embryogenesis.

2024-06-06 | GSE242851 | GEO

Effect of BMP4 and noggin on gene expression in murine R1 ES cells

Project description:To confirm that the SMAD1/5- and SMAD4-associated genes are direct transcriptional regulators in mESCs in response to BMP, we treated undifferentiated R1 ES cells with BMP4 or with the BMP4 antagonist noggin, which can inhibit BMP signaling effectively for 4 h. Undifferentiated R1 ES cells were treated for 4 h with BMP4 or with the BMP4 antagonist noggin, which can inhibit BMP signaling effectively. Untreated R1 ES cells served as the control.

2010-03-07 | E-GEOD-20527 | biostudies-arrayexpress

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