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Background <p>Genomic studies have linked single nucleotide variants in the enhancer region of the leukemia inhibitory factor receptor (<i>Lif</i>r) gene to chromatin accessibility and the regulation of self-renewal in mouse embryonic stem cells (mESCs). However, the underlying mechanisms remain unclear. This study investigates the role of the transcription factor BTB and CNC homology 1 (BACH1) in regulating the <i>Lifr</i> enhancer and its impact on mESC pluripotency.</p> Methods <p>We performed RNA-sequencing (RNA-seq) to assess the impact of <i>Bach1</i> knockout on gene expression in mESCs. Additionally, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and luciferase reporter gene analysis were employed to investigate the mechanism by which BACH1 regulates <i>Lifr</i> expression.</p> Results <p>Genomic analyses identified BACH1 binding at the <i>Lifr</i> enhancer proximal to rs50454566 in mESCs. Integrated single-cell RNA sequencing (scRNA-seq) data revealed co-upregulation of <i>Bach1</i> and <i>Lifr</i> in inner cell mass (ICM) cells. RNA-seq analyses demonstrated that <i>Bach1</i> depletion attenuated <i>Lifr</i> expression and impeded LIFR-signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, BACH1 recruited STAT3 to the <i>Lifr</i> enhancer, driving <i>Lifr</i> transcription and facilitating the LIFR-STAT3 signaling pathway, thereby enhancing mESC self-renewal.</p> Conclusion <p>Our findings demonstrate that BACH1 enhances <i>Lifr</i> enhancer activity by recruiting STAT3 and activates the LIFR-STAT3 signaling pathway by promoting the LIFR expression, thereby maintaining mESC self-renewal. Our results complement a novel insight into the regulatory role of BACH1 in maintaining the self-renewal capacity of mESCs.</p>

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BACH1 recruits STAT3 to enhance leukemia inhibitory factor receptor activity and augments the self-renewal capacity of mouse embryonic stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月2日

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  • Jinghua Ma,
  • Siyu Ma,
  • Cong Niu,
  • Siqing Wang,
  • Xiangxiang Wei,
  • Dan Meng,
  • Xiuling Zhi,
  • Jieyu Guo

摘要

Background

Genomic studies have linked single nucleotide variants in the enhancer region of the leukemia inhibitory factor receptor (Lifr) gene to chromatin accessibility and the regulation of self-renewal in mouse embryonic stem cells (mESCs). However, the underlying mechanisms remain unclear. This study investigates the role of the transcription factor BTB and CNC homology 1 (BACH1) in regulating the Lifr enhancer and its impact on mESC pluripotency.

Methods

We performed RNA-sequencing (RNA-seq) to assess the impact of Bach1 knockout on gene expression in mESCs. Additionally, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and luciferase reporter gene analysis were employed to investigate the mechanism by which BACH1 regulates Lifr expression.

Results

Genomic analyses identified BACH1 binding at the Lifr enhancer proximal to rs50454566 in mESCs. Integrated single-cell RNA sequencing (scRNA-seq) data revealed co-upregulation of Bach1 and Lifr in inner cell mass (ICM) cells. RNA-seq analyses demonstrated that Bach1 depletion attenuated Lifr expression and impeded LIFR-signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, BACH1 recruited STAT3 to the Lifr enhancer, driving Lifr transcription and facilitating the LIFR-STAT3 signaling pathway, thereby enhancing mESC self-renewal.

Conclusion

Our findings demonstrate that BACH1 enhances Lifr enhancer activity by recruiting STAT3 and activates the LIFR-STAT3 signaling pathway by promoting the LIFR expression, thereby maintaining mESC self-renewal. Our results complement a novel insight into the regulatory role of BACH1 in maintaining the self-renewal capacity of mESCs.