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Tbx3 controls Dppa3 levels to regulate exit from pluripotency towards mesodermal lineage

ABSTRACT: Tbx3, a member of the T-box family, plays important roles in development, stem cells, nuclear reprogramming and cancer. Loss of Tbx3 induces differentiation in mouse embryonic stem cells (mESCs). However, we show that mESCs exist in an alternate stable pluripotent state in the absence of Tbx3. In-depth transcriptome analysis of this mESC state reveals Dppa3 as a direct downstream target of Tbx3. Also Tbx3 facilitates the cell fate transition from pluripotent cells to mesoderm progenitors by directly repressing Wnt pathway members required for differentiation. Wnt signaling regulates differentiation of mESCs into mesoderm progenitors and helps maintain a naïve pluripotent state. We show that Tbx3, a downstream target of Wnt signaling, fine-tunes these divergent roles of Wnt signaling in mESCs. In conclusion, we identify a signaling-TF axis that controls the exit of mESCs from a self-renewing pluripotent state towards mesoderm differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE60066 | GEO | 2015/07/21

SECONDARY ACCESSION(S): PRJNA257405

REPOSITORIES: GEO

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Tbx3 controls Dppa3 levels to regulate exit from pluripotency towards mesodermal lineage

Project description:Tbx3, a member of the T-box family, plays important roles in development, stem cells, nuclear reprogramming and cancer. Loss of Tbx3 induces differentiation in mouse embryonic stem cells (mESCs). However, we show that mESCs exist in an alternate stable pluripotent state in the absence of Tbx3. In-depth transcriptome analysis of this mESC state reveals Dppa3 as a direct downstream target of Tbx3. Also Tbx3 facilitates the cell fate transition from pluripotent cells to mesoderm progenitors by directly repressing Wnt pathway members required for differentiation. Wnt signaling regulates differentiation of mESCs into mesoderm progenitors and helps maintain a naïve pluripotent state. We show that Tbx3, a downstream target of Wnt signaling, fine-tunes these divergent roles of Wnt signaling in mESCs. In conclusion, we identify a signaling-TF axis that controls the exit of mESCs from a self-renewing pluripotent state towards mesoderm differentiation. ChIPSeq and RNASeq (population and single cell) was performed on the indicated cell lines. Replicates are indicated as needed. The mm9 genome assembly was used. For single cell mRNA-Seq preparation, SSEA1+DAPI- mESCs were sorted and collected.

2015-07-21 | E-GEOD-60066 | biostudies-arrayexpress

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Project description:Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies focused on epigenetic factors that affect ESC self-renewal and pluripotency. Through our laboratory's previous studies on ESCs pluripotency, we found that Dppa3, as a Naive state marker gene, is of great significance to the transformation of mESCs pluripotency. However, the influence of overexpression of Dppa3 in ESCs on mESCs status has not been determined. Our results show that overexpression of Dppa3 induces global DNA demethylation, which is beneficial to the maintenance of pluripotency, but its differentiation ability is significantly impaired. In mESCs, Dppa3 regulates mESCs pluripotency by inhibiting de novo methylation pathway, maintaining methylation pathway, promoting demethylation pathway Tet2, up-regulating active histone modification and down-regulating heterogeneous histone modification. The 2C-like state of ESCs recapitulates key aspects of the two-cell stage mouse embryo both phenotypically and molecular, which providing a cellular model to investigate the progress of ZGA. Our results found Dppa3 promote facilitate 2C-state conversion.

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Project description:Serine/threonine kinase 40 (Stk40) was previously identified as a direct target gene of pluripotency-associated transcription factor Oct4 and its overexpression could facilitate differentiation of mouse embryonic stem cells (mESCs) towards the extraembryonic endoderm. Stk40-/- mice are lethal at the perinatal stage, displaying multiple organ failures. However, the molecular mechanisms underlying the physiological functions of Stk40 remain elusive. Here, we report that Stk40 ablation compromises the mesoderm differentiation from mESCs in vitro and in embryos. Mechanistically, Stk40 interacts with both mammalian constitutive photomorphogenic protein 1 (Cop1) and c-Jun, promoting degradation of c-Jun. Consequently, Stk40 knockout leads to c-Jun protein accumulation, which, in turn, might suppress the Wnt signaling activity and impair the mesoderm differentiation process. Overall, this study reveals that Stk40, together with Cop1, represent a novel axis for modulating c-Jun protein levels within an appropriate range during mesoderm differentiation from mESCs. Our finding provides new insight into the molecular mechanism regulating c-Jun protein stability and may have potential for managing related cellular disorders.

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ChIP-MS of DPPA3/STELLA in mouse embryonic stem cells

Project description:Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. So far, it was unclear how mammals specifically achieve global DNA hypomethylation, given the high conservation of the DNA (de-)methylation machinery among vertebrates. We found that DNA demethylation requires TET activity but mostly occurs at sites where TET proteins are not bound suggesting a rather indirect mechanism. Among the few specific genes bound and activated by TET proteins was the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella), which undergoes TDG dependent demethylation. The requirement of TET proteins for genome-wide DNA demethylation could be bypassed by ectopic expression of Dppa3. We show that DPPA3 binds and displaces UHRF1 from chromatin and thereby prevents the recruitment and activation of the maintenance DNA methyltransferase DNMT1. We demonstrate that DPPA3 alone can drive global DNA demethylation when transferred to amphibians (Xenopus) and fish (medaka), both species that naturally do not have a Dppa3 gene and exhibit no post-fertilization DNA demethylation. Our results show that TET proteins are responsible for active and - indirectly also for - passive DNA demethylation; while TET proteins initiate local and gene-specific demethylation in vertebrates, the recent emergence of DPPA3 introduced a unique means of genome-wide passive demethylation in mammals and contributed to the evolution of epigenetic regulation during early mammalian development.

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