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

  • Nat Commun. 2025 Feb 5;16(1):1377. doi: 10.1038/s41467-025-56608-0.
Yorihiro Iwasaki  1  2 ,  Monica Reyes  1 ,  Harald Jüppner  1  3 ,  Murat Bastepe  4
Affiliations
  • 1. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 2. Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
  • 3. Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 4. Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 39910084 DOI: 10.1038/s41467-025-56608-0
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.

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