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

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

Blog Article

Abstract Genomic imprinting controls parental allele-specific gene expression via epigenetic mechanisms.Abnormal imprinting at the GNAS gene causes multiple phenotypes, including Jandy LXi Parts 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 Bridle Bits 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.