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<p>Genomic imprinting controls parental allele-specific gene expression via epigenetic mechanisms. Abnormal imprinting at the <i>GNAS</i> gene causes multiple phenotypes, including pseudohypoparathyroidism type-1B (PHP1B), a disorder of multihormone resistance. Microdeletions affecting the neighboring <i>STX16</i> gene ablate an imprinting control region (STX16-ICR) of <i>GNAS</i> 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 <i>GNAS</i> parental allele and enhances two <i>GNAS</i> 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 <i>GNAS</i> 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 <i>GNAS</i> imprinting via different chromatin conformations, underlying the allele-specific pathogenicity of STX16-ICR microdeletions.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月5日

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  • Yorihiro Iwasaki,
  • Monica Reyes,
  • Harald Jüppner,
  • Murat Bastepe

摘要

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.