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

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

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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 Brooch 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 Wax Essentials 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.