Enhancer architecture-dependent multilayered transcriptional regulation orchestrates RA signal-induced early differentiation of ESC
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ABSTRACT:
PROVIDER: PRJNA715084 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13985600_1.fastq.gz | Fastqsanger.gz | |||
| SRR13985600_2.fastq.gz | Fastqsanger.gz | |||
| SRR13985601_1.fastq.gz | Fastqsanger.gz | |||
| SRR13985601_2.fastq.gz | Fastqsanger.gz | |||
| SRR13985602_1.fastq.gz | Fastqsanger.gz |
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Project description:Signaling pathway driven target gene transcriptions are critical for fate determination of embryonic stem cells (ESC), but enhancer architecture-dependent transcriptional regulation remains largely unclear in this process. Here, we described a complex enhancer architecture-dependent multilayered transcriptional regulation that orchestrates retinoic acid (RA) signal-induced early differentiation of ESC. Specifically, we identified Hoxa1 and lncRNA Halr1 as the direct downstream target genes of RA signal. Chromosome conformation capture based screens show that increased enhancer interactions promoted by RA signal are essential for Hoxa1 and Halr1 expressions during early ESC differentiation. Furthermore, we find that HOXA1 promotes Halr1 expression through direct binding to enhancers; conversely, absence of Halr1 RNA enhances interaction between Hoxa1 chromatin and multiple enhancers, but weakens interaction with HoxA cluster internal chromatin, thereby promoting RA signal-induced Hoxa1 overactivation and early differentiation of ESC. These results indicate that Halr1 binds to chromatin not only acts as a brake to orchestrate interaction between enhancers and Hoxa1 chromatin, but also acts as a binder to maintain chromatin interaction within HoxA cluster. In summary, these findings reveal a complex multilayered transcriptional regulation involving the synergistic regulation of enhancer, transcription factor and lncRNA, and that increases our understanding of the intrinsic molecular mechanisms of RA signal-induced ESC differentiation.
2021-04-16 | GSE169058 | GEO
Project description:Cells undergo fate transformation in response to external signaling stimuli, a process that depends on the precise expression of specific genes, but the intrinsic regulatory mechanisms remain largely unclear. Here, by integrating bulk RNA sequencing, single-cell RNA sequencing, 4D-SmartDIA quantitative proteomics data, and a CRISPR/Cas9-mediated RA receptor deletion model, we find that RA signaling-induced early ESC differentiation is multilineage. During early ESC differentiation, in the context of attenuated and enhanced RA signaling, we identified Cyp26 and HoxB cluster genes as its direct downstream targets. Upon activation of RA signaling, RA receptors induce new specific enhancers in the proximal/distal regions of cluster gene loci, whereas inhibition of RA signaling significantly reduces proximal/distal enhancer activity, chromatin accessibility and cluster gene expression. Mechanistically, we found that proximal/distal enhancers form specific chromatin loops with cluster gene loci under RA induction, and RA receptor deletion significantly reduces these chromatin interactions. Knockout of the proximal/distal enhancers inhibits cluster gene expression, thereby further disrupting RA-induced early ESC differentiation. In summary, our findings reveal an insightful mechanism underlying the signal-induced specific 3D genomic structure and cluster gene expression critical for early ESC fate transitions.
2026-04-20 | GSE276738 | GEO
Project description:Cells undergo fate transformation in response to external signaling stimuli, a process that depends on the precise expression of specific genes, but the intrinsic regulatory mechanisms remain largely unclear. Here, by integrating bulk RNA sequencing, single-cell RNA sequencing, 4D-SmartDIA quantitative proteomics data, and a CRISPR/Cas9-mediated RA receptor deletion model, we find that RA signaling-induced early ESC differentiation is multilineage. During early ESC differentiation, in the context of attenuated and enhanced RA signaling, we identified Cyp26 and HoxB cluster genes as its direct downstream targets. Upon activation of RA signaling, RA receptors induce new specific enhancers in the proximal/distal regions of cluster gene loci, whereas inhibition of RA signaling significantly reduces proximal/distal enhancer activity, chromatin accessibility and cluster gene expression. Mechanistically, we found that proximal/distal enhancers form specific chromatin loops with cluster gene loci under RA induction, and RA receptor deletion significantly reduces these chromatin interactions. Knockout of the proximal/distal enhancers inhibits cluster gene expression, thereby further disrupting RA-induced early ESC differentiation. In summary, our findings reveal an insightful mechanism underlying the signal-induced specific 3D genomic structure and cluster gene expression critical for early ESC fate transitions.
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Project description:Cells undergo fate transformation in response to external signaling stimuli, a process that depends on the precise expression of specific genes, but the intrinsic regulatory mechanisms remain largely unclear. Here, by integrating bulk RNA sequencing, single-cell RNA sequencing, 4D-SmartDIA quantitative proteomics data, and a CRISPR/Cas9-mediated RA receptor deletion model, we find that RA signaling-induced early ESC differentiation is multilineage. During early ESC differentiation, in the context of attenuated and enhanced RA signaling, we identified Cyp26 and HoxB cluster genes as its direct downstream targets. Upon activation of RA signaling, RA receptors induce new specific enhancers in the proximal/distal regions of cluster gene loci, whereas inhibition of RA signaling significantly reduces proximal/distal enhancer activity, chromatin accessibility and cluster gene expression. Mechanistically, we found that proximal/distal enhancers form specific chromatin loops with cluster gene loci under RA induction, and RA receptor deletion significantly reduces these chromatin interactions. Knockout of the proximal/distal enhancers inhibits cluster gene expression, thereby further disrupting RA-induced early ESC differentiation. In summary, our findings reveal an insightful mechanism underlying the signal-induced specific 3D genomic structure and cluster gene expression critical for early ESC fate transitions.
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Project description:Cells undergo fate transformation in response to external signaling stimuli, a process that depends on the precise expression of specific genes, but the intrinsic regulatory mechanisms remain largely unclear. Here, by integrating bulk RNA sequencing, single-cell RNA sequencing, 4D-SmartDIA quantitative proteomics data, and a CRISPR/Cas9-mediated RA receptor deletion model, we find that RA signaling-induced early ESC differentiation is multilineage. During early ESC differentiation, in the context of attenuated and enhanced RA signaling, we identified Cyp26 and HoxB cluster genes as its direct downstream targets. Upon activation of RA signaling, RA receptors induce new specific enhancers in the proximal/distal regions of cluster gene loci, whereas inhibition of RA signaling significantly reduces proximal/distal enhancer activity, chromatin accessibility and cluster gene expression. Mechanistically, we found that proximal/distal enhancers form specific chromatin loops with cluster gene loci under RA induction, and RA receptor deletion significantly reduces these chromatin interactions. Knockout of the proximal/distal enhancers inhibits cluster gene expression, thereby further disrupting RA-induced early ESC differentiation. In summary, our findings reveal an insightful mechanism underlying the signal-induced specific 3D genomic structure and cluster gene expression critical for early ESC fate transitions.
2026-04-20 | GSE315092 | GEO
Project description:Cells undergo fate transformation in response to external signaling stimuli, a process that depends on the precise expression of specific genes, but the intrinsic regulatory mechanisms remain largely unclear. Here, by integrating bulk RNA sequencing, single-cell RNA sequencing, 4D-SmartDIA quantitative proteomics data, and a CRISPR/Cas9-mediated RA receptor deletion model, we find that RA signaling-induced early ESC differentiation is multilineage. During early ESC differentiation, in the context of attenuated and enhanced RA signaling, we identified Cyp26 and HoxB cluster genes as its direct downstream targets. Upon activation of RA signaling, RA receptors induce new specific enhancers in the proximal/distal regions of cluster gene loci, whereas inhibition of RA signaling significantly reduces proximal/distal enhancer activity, chromatin accessibility and cluster gene expression. Mechanistically, we found that proximal/distal enhancers form specific chromatin loops with cluster gene loci under RA induction, and RA receptor deletion significantly reduces these chromatin interactions. Knockout of the proximal/distal enhancers inhibits cluster gene expression, thereby further disrupting RA-induced early ESC differentiation. In summary, our findings reveal an insightful mechanism underlying the signal-induced specific 3D genomic structure and cluster gene expression critical for early ESC fate transitions.
2026-04-20 | GSE276726 | GEO
Project description:Retinoic acid (RA) plays a pivotal role in different biological processes including inducing differentiation of embryonic stem cells (ESCs). We first knocked out one or both of RA receptors- Rarα and Rxrα to partially abolish the RA signaling, and then overexpressed one of them separately to hyper activation of RA signaling pathway. By transcriptome analysis, we show that RA signaling effects multi-lineage differentiation, particularly the endoderm, and identify RA signaling target genes, interesting, there are two family cluster genes- Hoxb and Cyp26. Chromosome immunoprecipitation (ChIP-seq) shows that RA induces novel proximal and distal enhancers around the cluster target genes and these enhancers are dependent of RA receptors(Rarα/Rxrα). 4C-seq reveals enhancer-enhancer and enhancer-promoter interactions in their regions and shows a decrease in the relative frequency of contact relative to WT after Rarα/Rxrα-knockout, suggesting Rarα/Rxrα participate in mediating chromatin interaction. We also identify that enhancers significantly maintain expression of RA-induced Hoxb and Cyp26 family genes and regulate multi-lineage marker genes. At the same time, we reveal that disrupting RA-response elements (RAREs) in the enhancer affects the expression of the target gene. Our study provides mechanistic insight into RA-induced early ESC differentiation to endoderm and potential regular regulation of downstream target genes.
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Project description:RA-dependent proximal and distal enhancers’ architecture promotes RA-induced early ESC differentiation
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Project description:To uncover the mechanism that Wnt signaling modulates RA-induced ESC differentiation, we conducted time course RNA-seq analysis during the differentiation. Transcriptome profiles of RA-induced and RA/CHIR-induced ESC differentiation were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The RNA-seq data revealed a significant decrease in mesoderm (one of the major source of vascular SMCs) markers and increase in PrE markers in CHIR treated samples, while other lineage markers showed no significant expression, implying a diverging to PrE fate by Wnt activation. Subsequent hierarchical clustering analysis also showed that the gene expression profiles of cells derived from RA induction alone clustered with adult SMCs, while cells derived from RA/CHIR induction gradually clustered to XEN cells with differentiation and was very close to XEN cells at day 16, suggesting that RA/CHIR-induced ESCs differentiated into PrE lineage. This study provided new insights into the importance of RA/Wnt crosstalk in the lineage differentiation of ESCs.
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Project description: Not available
| S-EPMC8599802 | biostudies-literature