A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations
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 neighborin...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56608-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861774073462784 |
|---|---|
| author | Yorihiro Iwasaki Monica Reyes Harald Jüppner Murat Bastepe |
| author_facet | Yorihiro Iwasaki Monica Reyes Harald Jüppner Murat Bastepe |
| author_sort | Yorihiro Iwasaki |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-00911723bfaa4ee7aa5bb7264d8e68e4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-00911723bfaa4ee7aa5bb7264d8e68e42025-02-09T12:44:49ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-56608-0A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformationsYorihiro Iwasaki0Monica Reyes1Harald Jüppner2Murat Bastepe3Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical SchoolEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical SchoolEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical SchoolEndocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical SchoolAbstract 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.https://doi.org/10.1038/s41467-025-56608-0 |
| spellingShingle | Yorihiro Iwasaki Monica Reyes Harald Jüppner Murat Bastepe A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations Nature Communications |
| title | A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations |
| title_full | A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations |
| title_fullStr | A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations |
| title_full_unstemmed | A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations |
| title_short | A biallelically active embryonic enhancer dictates GNAS imprinting through allele-specific conformations |
| title_sort | biallelically active embryonic enhancer dictates gnas imprinting through allele specific conformations |
| url | https://doi.org/10.1038/s41467-025-56608-0 |
| work_keys_str_mv | AT yorihiroiwasaki abiallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT monicareyes abiallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT haraldjuppner abiallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT muratbastepe abiallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT yorihiroiwasaki biallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT monicareyes biallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT haraldjuppner biallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations AT muratbastepe biallelicallyactiveembryonicenhancerdictatesgnasimprintingthroughallelespecificconformations |