BMP4 triggers regulatory circuits specifying the cardiac mesoderm lineage
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ABSTRACT:
PROVIDER: PRJNA708331 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13917400_1.fastq.gz | Fastqsanger.gz | |||
| SRR13917400_2.fastq.gz | Fastqsanger.gz | |||
| SRR13917401_1.fastq.gz | Fastqsanger.gz | |||
| SRR13917401_2.fastq.gz | Fastqsanger.gz | |||
| SRR13917402_1.fastq.gz | Fastqsanger.gz |
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Project description:Cardiac lineage specification in the mouse is controlled by TGFβ and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positive feedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1 establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during cardiac mesoderm specification.
2023-05-03 | GSE168580 | GEO
Project description:Cardiac lineage specification in the mouse is controlled by TGFβ and WNT signaling. From fly to fish, BMP has been identified as an indispensable heart inducer. A detailed analysis of the role of Bmp4 and its effectors Smad1/5, however, was still missing. We show that Bmp4 induces cardiac mesoderm formation in murine embryonic stem cells in vitro. Bmp4 first activates Wnt3 and upregulates Nodal. pSmad1/5 and the WNT effector Tcf3 form a complex, and together with pSmad2/3 activate mesoderm enhancers and Eomes. They then cooperate with Eomes to consolidate the expression of many mesoderm factors, including T. Eomes and T form a positive- feedback loop and open additional enhancers regulating early mesoderm genes, including the transcription factor Mesp1, establishing the cardiac mesoderm lineage. In parallel, the neural fate is suppressed. Our data confirm the pivotal role of Bmp4 in cardiac mesoderm formation in the mouse. We describe in detail the consecutive and cooperative actions of three signaling pathways, BMP, WNT and Nodal, and their effector transcription factors, during cardiac mesoderm specification.
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Project description:Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization. Canalization is essential for stabilizing cell fate, but mechanisms underlying robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state referred to as a saddle-node bifurcation. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of neurogenic factor POU3F1, preventing expression of neural suppressor REST, and disrupting composition of BRG1 complexes. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modeling supports all our observations. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1 mutant phenotypes, severely compromising cardiogenesis, unmasking an in vivo role for Brm. Our results reveal Brm as a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.
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Project description:Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and often associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators, we have analyzed the protein secretome of human endothelial cells in the presence of sEng. We find that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased levels of BMP4 transcripts in lungs and increased circulating BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appears 18 days after mating, precisely coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 are positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the pathobiology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
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Project description:The developing placenta, originated in the mouse through the extra-embryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet, unbiased characterization of ExE differentiation dynamics and interaction with the embryo proper remains incomplete. Here, we develop a temporal single-cell model of mouse gastrulation that maps continuous and parallel differentiation in embryonic and extraembryonic lineages. This is matched with a 3-way perturbation approach to target signaling from the embryo proper, the ExE alone, or both. We show that ExE specification involves early spatial and transcriptional bifurcation of uncommitted ectoplacental cone cells (EPCs) and chorion progenitors. Early BMP4 signaling from chorion progenitors is required for proper differentiation of uncommitted EPCs and later for their specification towards trophoblast giant cells. We also find bi-phasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper endo-mesoderm bifurcation, allantois, and primordial germ cells (PGCs) specification. However, commencing at E7.5, embryonic-derived BMP4 source restricts PGC pool size by favoring differentiation of their extraembryonic mesoderm precursors towards an allantois fate. ExE and embryonic tissues are therefore entangled in time, space, and signaling axes, highlighting the importance of their integrated understanding and modeling in vivo and in vitro.
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Project description:Mouse naive and primed pluripotent stem cells, ESC and EpiSC, represent two distinct stages of pluripotency. Here we report that BMP4 drives primed to naive transition or PNT by reprogramming chromatin accessibility. ATAC-seq reveals that a short pulse of BMP4 triggers EpiSCs to close 26409 and open 6428 loci to reach an intermediate state that continue to open 18744 and close 7042 loci under 2iL until reaching a naive state, following with a dramatic reactivation of the silenced X chromosome. Among loci opened by BMP4 are those encoding Id1, Tfap2c/2a and Zbtb7b that synergistically drive PNT without BMP4. Tfap2c-/- ESCs or EpiSCs self-renew normally, while the former capable of differentiating to the latter but the latter fails to undergo PNT, a defect rescuable by exogenous Tfap2c. Our results link BMP4 to PNT through a binary logic of chromatin closing and opening, revealing the intrinsic power of extracellular factors to reorganize nuclear architecture in development.
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