The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis
Summary: Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1’s demethylase and scaffolding functions during embryogenesis are not known. Here,...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222020107 |
| _version_ | 1828057163329699840 |
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| author | Mattie J. Casey Alexandra M. Call Annika V. Thorpe Cicely A. Jette Michael E. Engel Rodney A. Stewart |
| author_facet | Mattie J. Casey Alexandra M. Call Annika V. Thorpe Cicely A. Jette Michael E. Engel Rodney A. Stewart |
| author_sort | Mattie J. Casey |
| collection | DOAJ |
| description | Summary: Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1’s demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish lsd1/kdm1a mutant lines and show Lsd1 is required to repress primitive hematopoietic stem cell gene expression. Lsd1 rescue constructs containing point mutations that selectively abrogate its demethylase or scaffolding capacity demonstrate the scaffolding function of Lsd1, not its demethylase activity, is required for repression of gene expression in vivo. Lsd1’s SNAG-binding domain mediates its scaffolding function and reinforces a negative feedback loop to repress the expression of SNAG-domain-containing genes during embryogenesis, including gfi1 and snai1/2. Our findings reveal a model in which the SNAG-binding and scaffolding function of Lsd1, and its associated negative feedback loop, provide transient and reversible regulation of gene expression during hematopoietic development. |
| first_indexed | 2024-04-10T21:07:01Z |
| format | Article |
| id | doaj.art-e4086ce0d1e44269a796aa91edc20947 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-10T21:07:01Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-e4086ce0d1e44269a796aa91edc209472023-01-22T04:40:38ZengElsevieriScience2589-00422023-01-01261105737The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesisMattie J. Casey0Alexandra M. Call1Annika V. Thorpe2Cicely A. Jette3Michael E. Engel4Rodney A. Stewart5Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USADepartment of Pediatric Hematology/Oncology, Emily Couric Cancer Center, University of Virginia, Charlottesville, VA 22903, USA; Corresponding authorDepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, Salt Lake City, UT 84112, USA; Corresponding authorSummary: Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1’s demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish lsd1/kdm1a mutant lines and show Lsd1 is required to repress primitive hematopoietic stem cell gene expression. Lsd1 rescue constructs containing point mutations that selectively abrogate its demethylase or scaffolding capacity demonstrate the scaffolding function of Lsd1, not its demethylase activity, is required for repression of gene expression in vivo. Lsd1’s SNAG-binding domain mediates its scaffolding function and reinforces a negative feedback loop to repress the expression of SNAG-domain-containing genes during embryogenesis, including gfi1 and snai1/2. Our findings reveal a model in which the SNAG-binding and scaffolding function of Lsd1, and its associated negative feedback loop, provide transient and reversible regulation of gene expression during hematopoietic development.http://www.sciencedirect.com/science/article/pii/S2589004222020107Molecular biologyMolecular interactionCell biologyStem cells research |
| spellingShingle | Mattie J. Casey Alexandra M. Call Annika V. Thorpe Cicely A. Jette Michael E. Engel Rodney A. Stewart The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis iScience Molecular biology Molecular interaction Cell biology Stem cells research |
| title | The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| title_full | The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| title_fullStr | The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| title_full_unstemmed | The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| title_short | The scaffolding function of LSD1/KDM1A reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| title_sort | scaffolding function of lsd1 kdm1a reinforces a negative feedback loop to repress stem cell gene expression during primitive hematopoiesis |
| topic | Molecular biology Molecular interaction Cell biology Stem cells research |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222020107 |
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