Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells
The transcription factor Oct4 is essential for the maintenance and induction of stem cell pluripotency, but its functional roles are not fully understood. Here, we investigate the functions of Oct4 by depleting and subsequently recovering it in mouse embryonic stem cells (ESCs) and conducting a time...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-05-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/71533 |
| _version_ | 1811252164704600064 |
|---|---|
| author | Le Xiong Erik A Tolen Jinmi Choi Sergiy Velychko Livia Caizzi Taras Velychko Kenjiro Adachi Caitlin M MacCarthy Michael Lidschreiber Patrick Cramer Hans R Schöler |
| author_facet | Le Xiong Erik A Tolen Jinmi Choi Sergiy Velychko Livia Caizzi Taras Velychko Kenjiro Adachi Caitlin M MacCarthy Michael Lidschreiber Patrick Cramer Hans R Schöler |
| author_sort | Le Xiong |
| collection | DOAJ |
| description | The transcription factor Oct4 is essential for the maintenance and induction of stem cell pluripotency, but its functional roles are not fully understood. Here, we investigate the functions of Oct4 by depleting and subsequently recovering it in mouse embryonic stem cells (ESCs) and conducting a time-resolved multiomics analysis. Oct4 depletion leads to an immediate loss of its binding to enhancers, accompanied by a decrease in mRNA synthesis from its target genes that are part of the transcriptional network that maintains pluripotency. Gradual decrease of Oct4 binding to enhancers does not immediately change the chromatin accessibility but reduces transcription of enhancers. Conversely, partial recovery of Oct4 expression results in a rapid increase in chromatin accessibility, whereas enhancer transcription does not fully recover. These results indicate different concentration-dependent activities of Oct4. Whereas normal ESC levels of Oct4 are required for transcription of pluripotency enhancers, low levels of Oct4 are sufficient to retain chromatin accessibility, likely together with other factors such as Sox2. |
| first_indexed | 2024-04-12T16:30:45Z |
| format | Article |
| id | doaj.art-1d5965331e63415ea1891c5a5bf6e818 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:30:45Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-1d5965331e63415ea1891c5a5bf6e8182022-12-22T03:25:08ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.71533Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cellsLe Xiong0https://orcid.org/0000-0001-8180-768XErik A Tolen1https://orcid.org/0000-0002-7147-7506Jinmi Choi2Sergiy Velychko3https://orcid.org/0000-0002-6227-3966Livia Caizzi4https://orcid.org/0000-0001-9723-6893Taras Velychko5Kenjiro Adachi6Caitlin M MacCarthy7https://orcid.org/0000-0001-8434-5441Michael Lidschreiber8https://orcid.org/0000-0002-6740-2755Patrick Cramer9https://orcid.org/0000-0001-5454-7755Hans R Schöler10https://orcid.org/0000-0002-7422-8847Max Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, GermanyMax Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, GermanyMax Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, GermanyMax Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, GermanyMax Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Multidisciplinary Sciences, Department of Molecular Biology, Göttingen, GermanyMax Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Münster, GermanyThe transcription factor Oct4 is essential for the maintenance and induction of stem cell pluripotency, but its functional roles are not fully understood. Here, we investigate the functions of Oct4 by depleting and subsequently recovering it in mouse embryonic stem cells (ESCs) and conducting a time-resolved multiomics analysis. Oct4 depletion leads to an immediate loss of its binding to enhancers, accompanied by a decrease in mRNA synthesis from its target genes that are part of the transcriptional network that maintains pluripotency. Gradual decrease of Oct4 binding to enhancers does not immediately change the chromatin accessibility but reduces transcription of enhancers. Conversely, partial recovery of Oct4 expression results in a rapid increase in chromatin accessibility, whereas enhancer transcription does not fully recover. These results indicate different concentration-dependent activities of Oct4. Whereas normal ESC levels of Oct4 are required for transcription of pluripotency enhancers, low levels of Oct4 are sufficient to retain chromatin accessibility, likely together with other factors such as Sox2.https://elifesciences.org/articles/71533pluripotencyOct4enhancereRNAchromatin accessibilitygene regulation |
| spellingShingle | Le Xiong Erik A Tolen Jinmi Choi Sergiy Velychko Livia Caizzi Taras Velychko Kenjiro Adachi Caitlin M MacCarthy Michael Lidschreiber Patrick Cramer Hans R Schöler Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells eLife pluripotency Oct4 enhancer eRNA chromatin accessibility gene regulation |
| title | Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| title_full | Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| title_fullStr | Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| title_full_unstemmed | Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| title_short | Oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| title_sort | oct4 differentially regulates chromatin opening and enhancer transcription in pluripotent stem cells |
| topic | pluripotency Oct4 enhancer eRNA chromatin accessibility gene regulation |
| url | https://elifesciences.org/articles/71533 |
| work_keys_str_mv | AT lexiong oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT erikatolen oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT jinmichoi oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT sergiyvelychko oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT liviacaizzi oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT tarasvelychko oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT kenjiroadachi oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT caitlinmmaccarthy oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT michaellidschreiber oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT patrickcramer oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells AT hansrscholer oct4differentiallyregulateschromatinopeningandenhancertranscriptioninpluripotentstemcells |