High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle.
Evidence suggests the transcription factor GATA-2 is a critical regulator of murine hematopoietic stem cells. Here, we explore the relation between GATA-2 and cell proliferation and show that inducing GATA-2 increases quiescence (G(0) residency) of murine and human hematopoietic cells. In human cord...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2009
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| _version_ | 1797058270582538240 |
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| author | Tipping, A Pina, C Castor, A Hong, D Rodrigues, N Lazzari, L May, G Jacobsen, SE Enver, T |
| author_facet | Tipping, A Pina, C Castor, A Hong, D Rodrigues, N Lazzari, L May, G Jacobsen, SE Enver, T |
| author_sort | Tipping, A |
| collection | OXFORD |
| description | Evidence suggests the transcription factor GATA-2 is a critical regulator of murine hematopoietic stem cells. Here, we explore the relation between GATA-2 and cell proliferation and show that inducing GATA-2 increases quiescence (G(0) residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34(+)CD38(-)Hoechst(lo)Pyronin Y(lo)) express more GATA-2 than cycling counterparts. Enforcing GATA-2 expression increased quiescence of cord blood cells, reducing proliferation and performance in long-term culture-initiating cell and colony-forming cell (CFC) assays. Gene expression analysis places GATA-2 upstream of the quiescence regulator MEF, but enforcing MEF expression does not prevent GATA-2-conferred quiescence, suggesting additional regulators are involved. Although known quiescence regulators p21(CIP1) and p27(KIP1) do not appear to be responsible, enforcing GATA-2 reduced expression of regulators of cell cycle such as CCND3, CDK4, and CDK6. Enforcing GATA-2 inhibited human hematopoiesis in vivo: cells with highest exogenous expression (GATA-2(hi)) failed to contribute to hematopoiesis in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice, whereas GATA-2(lo) cells contributed with delayed kinetics and low efficiency, with reduced expression of Ki-67. Thus, GATA-2 activity inhibits cell cycle in vitro and in vivo, highlighting GATA-2 as a molecular entry point into the transcriptional program regulating quiescence in human hematopoietic stem and progenitor cells. |
| first_indexed | 2024-03-06T19:48:05Z |
| format | Journal article |
| id | oxford-uuid:2306a221-ec3d-4d52-933f-42719f6b2a27 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:48:05Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:2306a221-ec3d-4d52-933f-42719f6b2a272022-03-26T11:42:00ZHigh GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2306a221-ec3d-4d52-933f-42719f6b2a27EnglishSymplectic Elements at Oxford2009Tipping, APina, CCastor, AHong, DRodrigues, NLazzari, LMay, GJacobsen, SEEnver, TEvidence suggests the transcription factor GATA-2 is a critical regulator of murine hematopoietic stem cells. Here, we explore the relation between GATA-2 and cell proliferation and show that inducing GATA-2 increases quiescence (G(0) residency) of murine and human hematopoietic cells. In human cord blood, quiescent fractions (CD34(+)CD38(-)Hoechst(lo)Pyronin Y(lo)) express more GATA-2 than cycling counterparts. Enforcing GATA-2 expression increased quiescence of cord blood cells, reducing proliferation and performance in long-term culture-initiating cell and colony-forming cell (CFC) assays. Gene expression analysis places GATA-2 upstream of the quiescence regulator MEF, but enforcing MEF expression does not prevent GATA-2-conferred quiescence, suggesting additional regulators are involved. Although known quiescence regulators p21(CIP1) and p27(KIP1) do not appear to be responsible, enforcing GATA-2 reduced expression of regulators of cell cycle such as CCND3, CDK4, and CDK6. Enforcing GATA-2 inhibited human hematopoiesis in vivo: cells with highest exogenous expression (GATA-2(hi)) failed to contribute to hematopoiesis in nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice, whereas GATA-2(lo) cells contributed with delayed kinetics and low efficiency, with reduced expression of Ki-67. Thus, GATA-2 activity inhibits cell cycle in vitro and in vivo, highlighting GATA-2 as a molecular entry point into the transcriptional program regulating quiescence in human hematopoietic stem and progenitor cells. |
| spellingShingle | Tipping, A Pina, C Castor, A Hong, D Rodrigues, N Lazzari, L May, G Jacobsen, SE Enver, T High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title | High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title_full | High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title_fullStr | High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title_full_unstemmed | High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title_short | High GATA-2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle. |
| title_sort | high gata 2 expression inhibits human hematopoietic stem and progenitor cell function by effects on cell cycle |
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