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Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast ATAC-seq]

ABSTRACT: Tbx3 regulates liver development in the mouse, but it's role in human liver development is unclear. We generated TBX3 knockout pluripotent stem cell lines and found that liver differentiation is also impaired in humans. Interestingly we noted expression of pancreas-specific genes during the liver differentiation in the TBX3 knockout line. To further investigate this phenomenon, we performed ATAC-seq on cells at the hepatoblast stage of the liver differentiation. These studies demonstrated that the loss of TBX3 enhances pancreatic-gene signature, implicating TBX3 as a regulator of fate decisions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180527 | GEO | 2021/10/14

REPOSITORIES: GEO

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Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast RNA-seq]

Project description:Tbx3 regulates liver development in the mouse, but it's role in human liver development is unclear. We generated TBX3 knockout pluripotent stem cell lines and found that liver differentiation is also impaired in humans. Interestingly we noted expression of pancreas-specific genes during the liver differentiation in the TBX3 knockout line. To further investigate this phenomenon, we performed RNA-seq on cells at the hepatoblast stage of the liver differentiation. These studies demonstrated that the loss of TBX3 enhances pancreatic-gene signature, implicating TBX3 as a regulator of fate decisions.

2021-10-14 | GSE180526 | GEO

Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Pancreas RNA-seq]

Project description:Tbx3 regulates liver development in the mouse, but it's role in human liver development is unclear. We generated TBX3 knockout pluripotent stem cell lines and found that liver differentiation is also impaired in humans. Interestingly we noted expression of pancreas-specific genes during the liver differentiation in the TBX3 knockout line.To further investigate this phenomenon, we performed RNA-seq on cells from two stages of the pancreatic differentation. These studies demonstrated that the loss of TBX3 enhances pancreatic-gene signature, implicating TBX3 as a regulator of fate decisions.

2021-10-14 | GSE180525 | GEO

Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast ATAC-seq]

Project description:Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast ATAC-seq]

| PRJNA748593 | ENA

Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast RNA-seq]

Project description:Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells [Hepatoblast RNA-seq]

| PRJNA748592 | ENA

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis

Project description:MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

2024-02-19 | PXD049704 |

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

2024-04-15 | GSE255930 | GEO

Dynamics of chromatin marks and the role of EZH2/JMJD3/P300 during hepatoblast differentiation

Project description:Bi-potential hepatoblasts give rise to hepatocytes with the default fate choice, while undergo a regulatory fate transition to cholangiocytes. We aimed to understand how the “default” vs “regulatory” cell fate differentiations were modulated at the chromatin level. We performed chromatin immunoprecipitation sequencing (ChIP-seq) of hepatobiliary lineages to profile promoter and enhancer associated histone modifications H3K4me3, H3K27me3, H3K27ac and H3K4me1. We also performed in vivo gene manipulation and ex vivo intervention of related histone modifiers were performed to validate their roles in hepatoblast differentiation. We discovered that removal of H3K27me3 from bivalency on promoters was associated with activation of genes related to hepatoblast-cholangiocyte fate transition. In vivo gene manipulation and ex vivo intervention with H3K27me3-modifying enzymes demonstrated that Ezh2 and Jmjd3 specifically regulated hepatoblast-cholangiocyte cell fate transition. In addition, establishments of active and primed enhancers were associated with the developmental processes of both hepatocytes and cholangiocytes, and knockout of P300 inhibited these lineages development.

2023-06-26 | GSE142089 | GEO

A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation

Project description:How the bi-potential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from E10.5 to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, the proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine the single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) signaling pathway promoted cholangiocyte maturation. CONCLUSIONS: Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate towards specific hepatic cell fates in vitro.

2017-07-14 | GSE90047 | GEO

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

TBX3 defines the functional identity of hypothalamic melanocortin neurons

Project description:Purpose: Identify cellular pathways controlled by Tbx3 Methods: RNA sequencing of hypothalamic primary neurons from Tbx3 loxP/loxP mice infected with Ad-Cre or Ad-GFP viruses. Results: Unbiased pathway analysis revealed that Tbx3 deletion in primary neurons significantly affected the expression of genes involved in several pathways responsible for controlling cellular proliferation, differentiation and determination of cellular fate. Conclusions: Tbx3 in primary neurons might be implicated in the development and maintenance of neuronal identity.

2019-01-22 | GSE119883 | GEO

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