ArticleNucleic acids research2021
Enhancer architecture-dependent multilayered transcriptional regulation orchestrates RA signaling-induced early lineage differentiation of ESCs.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 9 citations in OpenAlex.
- ANRIL in Cardiovascular Diseases: Expression, Mechanism and Therapeutic Implications.Cardiovascular drugs and therapy · 2026Review
- Klf5-adjacent super-enhancer functions as a 3D genome structure-dependent transcriptional driver to safeguard ESC identity.Nature communications · 2025Article
- Long noncoding RNA as an emerging regulator of endoderm differentiation: progress and perspectives.Cell regeneration (London, England) · 2025Review
- Synergistic potential of stem cells and microfluidics in regenerative medicine.Molecular and cellular biochemistry · 2025Review
- LncRNA HOXB-AS4 Promotes Tumor Malignant Phenotype in Head and Neck Squamous Cell Carcinoma and Serves as a Prognosis Marker.Journal of Cancer · 2025Article
- Single cell-spatial transcriptomics and bulk multi-omics analysis of heterogeneity and ecosystems in hepatocellular carcinoma.NPJ precision oncology · 2024Article
- Genetic association ofTranslational pediatrics · 2024Article
- Transcription regulation by long non-coding RNAs: mechanisms and disease relevance.Nature reviews. Molecular cell biology · 2024Review
- Rewiring of the epigenome and chromatin architecture by exogenously induced retinoic acid signaling during zebrafish embryonic development.Nucleic acids research · 2024Article
- LINC MIR503HG Controls SC-β Cell Differentiation and Insulin Production by Targeting CDH1 and HES1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Signaling pathway-driven target gene transcription is critical for fate determination of embryonic stem cells (ESCs), but enhancer-dependent transcriptional regulation in these processes remains poorly understood. Here, we report enhancer architecture-dependent multilayered transcriptional regulation at the Halr1-Hoxa1 locus that orchestrates retinoic acid (RA) signaling-induced early lineage differentiation of ESCs. We show that both homeobox A1 (Hoxa1) and Hoxa adjacent long non-coding RNA 1 (Halr1) are identified as direct downstream targets of RA signaling and regulated by RARA/RXRA via RA response elements (RAREs). Chromosome conformation capture-based screens indicate that RA signaling promotes enhancer interactions essential for Hoxa1 and Halr1 expression and mesendoderm differentiation of ESCs. Furthermore, the results also show that HOXA1 promotes expression of Halr1 through binding to enhancer; conversely, loss of Halr1 enhances interaction between Hoxa1 chromatin and four distal enhancers but weakens interaction with chromatin inside the HoxA cluster, leading to RA signaling-induced Hoxa1 overactivation and enhanced endoderm differentiation. These findings reveal complex transcriptional regulation involving synergistic regulation by enhancers, transcription factors and lncRNA. This work provides new insight into intrinsic molecular mechanisms underlying ESC fate determination during RA signaling-induced early differentiation.
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