Tbx1 stabilizes differentiation of the cardiopharyngeal mesoderm and drives morphogenesis in the pharyngeal apparatus.
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PROVIDER: PRJEB64050 | ENA |
REPOSITORIES: ENA
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Project description:In the heart development, mesodermal progenitor cells in pharyngeal apparatus, termed cardiopharyngeal mesoderm, contribute to both atruim and right ventricle. Tbx1 gene, encoding a T-box transctiption factor and gene haploinsufficient in 22q11.2 deletion syndrome, is required for cardiac outflow tranct and branchiomeric muscle development. To understand how TBX1 affect open chromatin status in cardiopharyngeal mesoderm, we performed ATAC-seq in Tbx1-Cre lineage with/without Tbx1 expression.
2021-10-10 | GSE173700 | GEO
Project description:Hemizygous microdeletions on chromosome 22q11.2 cause a broad spectrum of congenital cardiovascular and craniofacial anomalies known collectively as DiGeorge Syndrome (DGS) that appear to arise from reduced expression of TBX1, a gene in the typically deleted region. Although mice lacking tbx1 display similar, yet more severe, cardiovascular and craniofacial defects, the mechanisms underlying these devastating phenotypes remain incompletely understood. Here, we report that Tbx1 is required prior to pharyngeal arch development to specify the nkx2.5+ cardiopharyngeal cell lineage that gives rise to the cardiovascular and crainiofacial structures absent in tbx1 null zebrafish. Importantly, the role of Tbx1 during cardiopharyngeal lineage specification is conserved in mammals. Further, we learned that DVR1, the zebrafish homolog of mammalian GDF1/3, functions downstream of Tbx1 for pharyngeal progenitor specification. Together, these studies unveil a new paradigm potentially underlying the cardiovascular and craniofacial defects observed in the DGS population.
2018-07-31 | GSE103120 | GEO
Project description:The heart and branchiomeric muscles are formed from the cardiopharyngeal mesoderm (CPM) during mammalian embryogenesis. The molecular mechanisms for lineage progression in the CPM in mammals remain elusive. Here, we have used single cell RNA-seq and lineage analysis and identified a cardiopharyngeal niche containing multilineage primed cells termed multilineage progenitors (MLPs), which is maintained throughout maturation of the pharyngeal apparatus. We found that MLP function is dependent on Tbx1, encoding a T-box transcription factor and the gene for 22q11.2 deletion syndrome. TBX1 positively regulates novel MLP enriched genes such as Aplnr and Nrg1, as well as known CPM genes related to both BrM and cardiac muscle cell development. Further, loss of Tbx1 results in ectopic expression of neuronal and other non-mesodermal specification genes such as Bdnf and Pax8, respectively, indicating that normal developmental regulation is disrupted. Integration of the multi-omic data generated a TBX1 gene regulatory network, including Isl1, Pitx2, Foxc2, Six1/2 and Tcf21, that regulates CPM lineage progression from MLPs. Our finding suggests that TBX1 is a one of the key regulators in MLP to maintain CPM property and promote differentiation toward both BrM and cardiac muscle cells.
2021-10-10 | GSE167491 | GEO
Project description:The heart and branchiomeric muscles are formed from the cardiopharyngeal mesoderm (CPM) during mammalian embryogenesis. The molecular mechanisms for lineage progression in the CPM in mammals remain elusive. Here, we have used single cell RNA-seq and lineage analysis and identified a cardiopharyngeal niche containing multilineage primed cells termed multilineage progenitors (MLPs), which is maintained throughout maturation of the pharyngeal apparatus. We found that MLP function is dependent on Tbx1, encoding a T-box transcription factor and the gene for 22q11.2 deletion syndrome. TBX1 positively regulates novel MLP enriched genes such as Aplnr and Nrg1, as well as known CPM genes related to both BrM and cardiac muscle cell development. Further, loss of Tbx1 results in ectopic expression of neuronal and other non-mesodermal specification genes such as Bdnf and Pax8, respectively, indicating that normal developmental regulation is disrupted. Integration of the multi-omic data generated a TBX1 gene regulatory network, including Isl1, Pitx2, Foxc2, Six1/2 and Tcf21, that regulates CPM lineage progression from MLPs. Our finding suggests that TBX1 is a one of the key regulators in MLP to maintain CPM property and promote differentiation toward both BrM and cardiac muscle cells.
2021-11-01 | GSE186934 | GEO
Project description:The heart and branchiomeric muscles are formed from the cardiopharyngeal mesoderm (CPM) during mammalian embryogenesis. The molecular mechanisms for lineage progression in the CPM in mammals remain elusive. Here, we have used single cell RNA-seq and lineage analysis and identified a cardiopharyngeal niche containing multilineage primed cells termed multilineage progenitors (MLPs), which is maintained throughout maturation of the pharyngeal apparatus. We found that MLP function is dependent on Tbx1, encoding a T-box transcription factor and the gene for 22q11.2 deletion syndrome. TBX1 positively regulates novel MLP enriched genes such as Aplnr and Nrg1, as well as known CPM genes related to both BrM and cardiac muscle cell development. Further, loss of Tbx1 results in ectopic expression of neuronal and other non-mesodermal specification genes such as Bdnf and Pax8, respectively, indicating that normal developmental regulation is disrupted. Integration of the multi-omic data generated a TBX1 gene regulatory network, including Isl1, Pitx2, Foxc2, Six1/2 and Tcf21, that regulates CPM lineage progression from MLPs. Our finding suggests that TBX1 is a one of the key regulators in MLP to maintain CPM property and promote differentiation toward both BrM and cardiac muscle cells.
2021-10-10 | GSE168768 | GEO
Project description:The heart and branchiomeric muscles are formed from the cardiopharyngeal mesoderm (CPM) during mammalian embryogenesis. The molecular mechanisms for lineage progression in the CPM in mammals remain elusive. Here, we have used single cell RNA-seq and lineage analysis and identified a cardiopharyngeal niche containing multilineage primed cells termed multilineage progenitors (MLPs), which is maintained throughout maturation of the pharyngeal apparatus. We found that MLP function is dependent on Tbx1, encoding a T-box transcription factor and the gene for 22q11.2 deletion syndrome. TBX1 positively regulates novel MLP enriched genes such as Aplnr and Nrg1, as well as known CPM genes related to both BrM and cardiac muscle cell development. Further, loss of Tbx1 results in ectopic expression of neuronal and other non-mesodermal specification genes such as Bdnf and Pax8, respectively, indicating that normal developmental regulation is disrupted. Integration of the multi-omic data generated a TBX1 gene regulatory network, including Isl1, Pitx2, Foxc2, Six1/2 and Tcf21, that regulates CPM lineage progression from MLPs. Our finding suggests that TBX1 is a one of the key regulators in MLP to maintain CPM property and promote differentiation toward both BrM and cardiac muscle cells.
2021-10-10 | GSE158941 | GEO
Project description:Dynamic gene expression programs determine multipotent cell states and fate choices during development. Multipotent progenitors for cardiomyocytes and branchiomeric head muscles populate the pharyngeal mesoderm of vertebrate embryos, but the mechanisms underlying cardiopharyngeal multipotency and heart vs. head muscle fate choices remain elusive. The tunicate Ciona emerged as a simple chordate model to study cardiopharyngeal development with unprecedented spatio-temporal resolution. We analyzed the transcriptome of single cardiopharyngeal lineage cells isolated at successive time points encompassing the transitions from multipotent progenitors to distinct first and second heart, and pharyngeal muscle precursors. We reconstructed the three cardiopharyngeal developmental trajectories, and characterized gene expression dynamics and regulatory states underlying each fate choice. Experimental perturbations and bulk transcriptome analyses revealed that ongoing FGF/MAPK signaling maintains cardiopharyngeal multipotency and promotes the pharyngeal muscle fate, whereas signal termination permits the deployment of a full pan-cardiac program and heart fate specification. We identified the Dach1/2 homolog as a novel evolutionarily conserved second-heart-field-specific factor and demonstrate, through lineage tracing and CRISPR/Cas9 perturbations, that it operates downstream of Tbx1/10 to actively suppress the first heart lineage program. This data indicates that the regulatory state of multipotent cardiopharyngeal progenitors determines the first vs. second heart lineage choice, and that Tbx1/10 acts as a bona fide regulator of cardiopharyngeal multi potency. 1823 FACS purified Ciona cardiopharyngeal progenitor cells at successive developmental stages (12, 14, 16, 18, 20 hpfs) have been sequenced in this research, encompassing the developmental spectrum from single multipotent progenitors to diverse fate-restricted progenitor cells. 1796 out of 1823 cells have reads successfully mapped to Ciona genome (i.e only 1796 samples have FPKM data in the *txt processed data files). We adopted multiple quality control criteria to filter out low quality single cell transcriptomes, the contaminating subpopulations and the doublets. Eventually, 848 high-quality cells were retained for further analysis. Based on previously identified cell type specific markers and the well established lineage tree, we identified all five cardiopharyngeal progenitor subtypes (TVC, STVC, ASM, FHP, SHP) and in silico reconstructed three unidirectional trajectories corresponding to the specification of pharyngeal and cardiac fate. Our study enabled us to characterize the global gene expression patterns of heterogeneous cardiopharyngeal progenitors, and interrogate the spatial-temporal dynamics of cardiopharyngeal specification.
2017-06-15 | GSE99844 | GEO
Project description:Approximately 60-70% of patients with 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome) have cardiac outflow tract anomalies including persistent truncus arteriosus (PTA) as the most severe defect. Among the genes in the 22q11.2 region, TBX1, encoding a T-box transcription factor is a major candidate for cardiovascular malformations and its inactivation in mice results in a PTA. To identify novel signaling mechanisms that function downstream, we found that Tbx1 restricts canonical Wnt signaling in the pharyngeal apparatus. To test for tissue specificity within the pharyngeal apparatus, we inactivated Tbx1 in the anterior portion of the secondary heart field (AHF) mesoderm using the Mef2c-AHF-Cre allele and observed a full penetrant PTA (n = 30). Tbx1 promotes progenitor cells but restricts differentiation whereas Wnt signaling, in the AHF, promotes cardiomyocyte differentiation. To determine whether Tbx1 and canonical Wnt signaling act in opposing pathways, both alleles of Tbx1 and one β-catenin allele were inactivated in the AHF and 85% of them (n = 35) showed partial or complete rescue. The antagonistic function of the two pathways was further confirmed by gene expression profiling, indicating that these two pathways provide a key balance in the AHF to prevent premature differentiation of progenitor cells prior to reaching the cardiac outflow tract. We inactivatedTbx1 and beta-catenin allele to identify function of Tbx1 and beta-catenin in the anterior portion of the secondary heart field (AHF) mesoderm. We also inactivated both alleles of Tbx1 and one β-catenin alleles (rescue design) to determine whether Tbx1 and canonical Wnt signaling act in opposing pathways
2016-09-01 | E-GEOD-78125 | biostudies-arrayexpress
Project description:During development, stem and progenitor cells divide and transition through germ layer- and lineage-specific multipotent states to generate the diverse cell types that compose an animal. Defined changes in biomolecular composition underlie the progressive loss of potency and acquisition of lineage-specific characteristics. For example, multipotent cardiopharyngeal progenitors display multilineage transcriptional priming, whereby both the cardiac and pharyngeal muscle programs are partially active and coexist in the same progenitor cells, while their daughter cells engage in a cardiac or pharyngeal muscle differentiation path only after cell division. Here, using the tunicate Ciona, we studied the acquisition of multilineage competence and the coupling between fate decisions and cell cycle progression. We showed that multipotent cardiopharyngeal progenitors acquire the competence to produce distinct Tbx1/10 (+) and (-) daughter cells shortly before mitosis, which is necessary for Tbx1/10 activation. By combining transgene-based sample barcoding with single cell RNA-seq (scRNA-seq), we uncovered transcriptome-wide dynamics in migrating cardiopharyngeal progenitors as cells progress through G1, S and G2 phases. We termed this process “transcriptome maturation”, and identified candidate “mature genes”, including the Rho GAP-coding gene Depdc1, which peak in late G2. Functional assays indicated that transcriptome maturation fosters cardiopharyngeal competence, in part through multilineage priming and proper oriented and asymmetric division that influences subsequent fate decisions, illustrating the concept of “behavioral competence”. Both classic feedforward circuits and coupling with cell cycle progression drive transcriptome maturation, uncovering distinct levels of coupling between cell cycle progression and fateful molecular transitions. We propose that coupling competence and fate decision with the G2 and G1 phases, respectively, ensures the timely deployment of lineage-specific programs.
2024-08-12 | GSE274445 | GEO
Project description:Approximately 60-70% of patients with 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome) have cardiac outflow tract anomalies including persistent truncus arteriosus (PTA) as the most severe defect. Among the genes in the 22q11.2 region, TBX1, encoding a T-box transcription factor is a major candidate for cardiovascular malformations and its inactivation in mice results in a PTA. To identify novel signaling mechanisms that function downstream, we found that Tbx1 restricts canonical Wnt signaling in the pharyngeal apparatus. To test for tissue specificity within the pharyngeal apparatus, we inactivated Tbx1 in the anterior portion of the secondary heart field (AHF) mesoderm using the Mef2c-AHF-Cre allele and observed a full penetrant PTA (n = 30). Tbx1 promotes progenitor cells but restricts differentiation whereas Wnt signaling, in the AHF, promotes cardiomyocyte differentiation. To determine whether Tbx1 and canonical Wnt signaling act in opposing pathways, both alleles of Tbx1 and one β-catenin allele were inactivated in the AHF and 85% of them (n = 35) showed partial or complete rescue. The antagonistic function of the two pathways was further confirmed by gene expression profiling, indicating that these two pathways provide a key balance in the AHF to prevent premature differentiation of progenitor cells prior to reaching the cardiac outflow tract.
2016-09-01 | GSE78125 | GEO