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TBX3 advances the developmental chromatin landscape towards the hepatic fate

ABSTRACT: TBX3 advances the developmental chromatin landscape towards the hepatic fate

PROVIDER: PRJNA1002354 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR25423701_1.fastq.gz	Fastqsanger.gz
	SRR25423701_2.fastq.gz	Fastqsanger.gz
	SRR25423702_1.fastq.gz	Fastqsanger.gz
	SRR25423702_2.fastq.gz	Fastqsanger.gz

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TBX3 advances the developmental chromatin landscape towards the hepatic fate [ChIP-seq]

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TBX3 advances the developmental chromatin landscape towards the hepatic fate [RNA-seq]

Project description:Hepatocytes differentiate from definitive endoderm in response to external signaling cues, however it is unclear how the hepatic lineage is specified and how transcription factors shape the chromatin to allow gene expression. By mapping histone modifications using a human stem cell model of hepatic differentiation, enhancers were found to exhibit dynamic, stage specific regulation, with many primed at the definitive endoderm stage. While hepatic enhancers gained active histone modifications, non-hepatic enhancers lost H3K4me1 after hepatic specification. TBX3, and to lesser extend HNF4A, bound to the hepatic enhancers and formed an interdependent transcription factor network. TBX3 bound both hepatic enhancers and promoters with low levels of H3K4me1 and a strong TBX3 motif. However, TBX3 binding was transient and upon eviction from TBX3-bound regions, H3K4me1 increased at enhancers, while H3K4me3 was established at promoters. This suggests that TBX3 plays a role in identifying hepatic enhancers and promoters during specification, which will then be activated to drive cell idenity.

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TBX3 advances the developmental chromatin landscape towards the hepatic fate

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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.

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