PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells
Summary: MSI2, which is expressed predominantly in hematopoietic stem and progenitor cells (HSPCs), enforces HSPC expansion when overexpressed and is upregulated in myeloid leukemias, indicating its regulated transcription is critical to balanced self-renewal and leukemia restraint. Despite this, li...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-04-01
|
| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671118301334 |
| _version_ | 1811217914879016960 |
|---|---|
| author | Muluken S. Belew Sonam Bhatia Ava Keyvani Chahi Stefan Rentas Jonathan S. Draper Kristin J. Hope |
| author_facet | Muluken S. Belew Sonam Bhatia Ava Keyvani Chahi Stefan Rentas Jonathan S. Draper Kristin J. Hope |
| author_sort | Muluken S. Belew |
| collection | DOAJ |
| description | Summary: MSI2, which is expressed predominantly in hematopoietic stem and progenitor cells (HSPCs), enforces HSPC expansion when overexpressed and is upregulated in myeloid leukemias, indicating its regulated transcription is critical to balanced self-renewal and leukemia restraint. Despite this, little is understood of the factors that enforce appropriate physiological levels of MSI2 in the blood system. Here, we define a promoter region that reports on endogenous expression of MSI2 and identify USF2 and PLAG1 as transcription factors whose promoter binding drives reporter activity. We show that these factors co-regulate, and are required for, efficient transactivation of endogenous MSI2. Coincident overexpression of USF2 and PLAG1 in primitive cord blood cells enhanced MSI2 transcription and yielded cellular phenotypes, including expansion of CD34+ cells in vitro, consistent with that achieved by direct MSI2 overexpression. Global chromatin immunoprecipitation sequencing analyses confirm a preferential co-binding of PLAG1 and USF2 at the promoter of MSI2, as well as regulatory regions corresponding to genes with roles in HSPC homeostasis. PLAG1 and USF2 cooperation is thus an important contributor to stem cell-specific expression of MSI2 and HSPC-specific transcriptional circuitry. : MSI2 is an essential human hematopoietic stem and progenitor cell (HSPC) regulator, but knowledge of the mechanisms ensuring its appropriate expression in this context are lacking. Here, Hope and colleagues map the MSI2 promoter functional in hematopoietic cells and identify USF2 and PLAG1 as essential, cooperative enforcers of endogenous MSI2 expression and stemness traits in human HSPCs. Keywords: human hematopoietic stem cells, self-renewal, promoter, transcriptional regulation, transcription factors, Musashi-2, genome-wide DNA binding site mapping, PLAG1, USF2 |
| first_indexed | 2024-04-12T07:01:53Z |
| format | Article |
| id | doaj.art-696a4f9d5be34658b2a9828b04d556c1 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-04-12T07:01:53Z |
| publishDate | 2018-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-696a4f9d5be34658b2a9828b04d556c12022-12-22T03:42:59ZengElsevierStem Cell Reports2213-67112018-04-0110413841397PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor CellsMuluken S. Belew0Sonam Bhatia1Ava Keyvani Chahi2Stefan Rentas3Jonathan S. Draper4Kristin J. Hope5Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, CanadaDepartment of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, CanadaDepartment of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, CanadaDepartment of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, CanadaDepartment of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, CanadaDepartment of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada; Corresponding authorSummary: MSI2, which is expressed predominantly in hematopoietic stem and progenitor cells (HSPCs), enforces HSPC expansion when overexpressed and is upregulated in myeloid leukemias, indicating its regulated transcription is critical to balanced self-renewal and leukemia restraint. Despite this, little is understood of the factors that enforce appropriate physiological levels of MSI2 in the blood system. Here, we define a promoter region that reports on endogenous expression of MSI2 and identify USF2 and PLAG1 as transcription factors whose promoter binding drives reporter activity. We show that these factors co-regulate, and are required for, efficient transactivation of endogenous MSI2. Coincident overexpression of USF2 and PLAG1 in primitive cord blood cells enhanced MSI2 transcription and yielded cellular phenotypes, including expansion of CD34+ cells in vitro, consistent with that achieved by direct MSI2 overexpression. Global chromatin immunoprecipitation sequencing analyses confirm a preferential co-binding of PLAG1 and USF2 at the promoter of MSI2, as well as regulatory regions corresponding to genes with roles in HSPC homeostasis. PLAG1 and USF2 cooperation is thus an important contributor to stem cell-specific expression of MSI2 and HSPC-specific transcriptional circuitry. : MSI2 is an essential human hematopoietic stem and progenitor cell (HSPC) regulator, but knowledge of the mechanisms ensuring its appropriate expression in this context are lacking. Here, Hope and colleagues map the MSI2 promoter functional in hematopoietic cells and identify USF2 and PLAG1 as essential, cooperative enforcers of endogenous MSI2 expression and stemness traits in human HSPCs. Keywords: human hematopoietic stem cells, self-renewal, promoter, transcriptional regulation, transcription factors, Musashi-2, genome-wide DNA binding site mapping, PLAG1, USF2http://www.sciencedirect.com/science/article/pii/S2213671118301334 |
| spellingShingle | Muluken S. Belew Sonam Bhatia Ava Keyvani Chahi Stefan Rentas Jonathan S. Draper Kristin J. Hope PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells Stem Cell Reports |
| title | PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells |
| title_full | PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells |
| title_fullStr | PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells |
| title_full_unstemmed | PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells |
| title_short | PLAG1 and USF2 Co-regulate Expression of Musashi-2 in Human Hematopoietic Stem and Progenitor Cells |
| title_sort | plag1 and usf2 co regulate expression of musashi 2 in human hematopoietic stem and progenitor cells |
| url | http://www.sciencedirect.com/science/article/pii/S2213671118301334 |
| work_keys_str_mv | AT mulukensbelew plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells AT sonambhatia plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells AT avakeyvanichahi plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells AT stefanrentas plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells AT jonathansdraper plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells AT kristinjhope plag1andusf2coregulateexpressionofmusashi2inhumanhematopoieticstemandprogenitorcells |