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A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations

Author

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  • Yorihiro Iwasaki

    (Massachusetts General Hospital and Harvard Medical School
    Kitano Hospital)

  • Monica Reyes

    (Massachusetts General Hospital and Harvard Medical School)

  • Harald Jüppner

    (Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Murat Bastepe

    (Massachusetts General Hospital and Harvard Medical School)

Abstract

Genomic imprinting controls parental allele-specific gene expression via epigenetic mechanisms. Abnormal imprinting at the GNAS gene causes multiple phenotypes, including pseudohypoparathyroidism type-1B (PHP1B), a disorder of multihormone resistance. Microdeletions affecting the neighboring STX16 gene ablate an imprinting control region (STX16-ICR) of GNAS and lead to PHP1B upon maternal but not paternal inheritance. Mechanisms behind this imprinted inheritance mode remain unknown. Here, we show that the STX16-ICR forms different chromatin conformations with each GNAS parental allele and enhances two GNAS promoters in human embryonic stem cells. When these cells differentiate toward proximal renal tubule cells, STX16-ICR loses its effect, accompanied by a transition to a somatic cell-specific GNAS imprinting status. The activity of STX16-ICR depends on an OCT4 motif, whose disruption impacts transcript levels differentially on each allele. Therefore, a biallelically active embryonic enhancer dictates GNAS imprinting via different chromatin conformations, underlying the allele-specific pathogenicity of STX16-ICR microdeletions.

Suggested Citation

  • Yorihiro Iwasaki & Monica Reyes & Harald Jüppner & Murat Bastepe, 2025. "A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56608-0
    DOI: 10.1038/s41467-025-56608-0
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    1. Liang Liang & Changchang Cao & Lei Ji & Zhaokui Cai & Di Wang & Rong Ye & Juan Chen & Xiaohua Yu & Jie Zhou & Zhibo Bai & Ruoyan Wang & Xianguang Yang & Ping Zhu & Yuanchao Xue, 2023. "Complementary Alu sequences mediate enhancer–promoter selectivity," Nature, Nature, vol. 619(7971), pages 868-875, July.
    2. Liang Liang & Changchang Cao & Lei Ji & Zhaokui Cai & Di Wang & Rong Ye & Juan Chen & Xiaohua Yu & Jie Zhou & Zhibo Bai & Ruoyan Wang & Xianguang Yang & Ping Zhu & Yuanchao Xue, 2023. "Publisher Correction: Complementary Alu sequences mediate enhancer–promoter selectivity," Nature, Nature, vol. 620(7975), pages 26-26, August.
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